Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization

Eilers, Grant; Gupta, Kushol; Allen, Audrey; Montermoso, Saira; Murali, Hemma; Sharp, Robert; Hwang, Young; Bushman, Frederic D.; Van Duyne, Gregory

doi:10.1371/journal.ppat.1011097

Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization

Journal Article · Fri Mar 03 00:00:00 EST 2023 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1011097· OSTI ID:2470320

Eilers, Grant ^[1]; ^[1]; Allen, Audrey ^[1]; Montermoso, Saira ^[1]; Murali, Hemma ^[1]; Sharp, Robert ^[1]; Hwang, Young ^[1]; Bushman, Frederic D. ^[1]; Van Duyne, Gregory ^[1]

Univ. of Pennsylvania, Philadelphia, PA (United States)

HIV integrase (IN) inserts viral DNA into the host genome and is the target of the strand transfer inhibitors (STIs), a class of small molecules currently in clinical use. Another potent class of antivirals is the allosteric inhibitors of integrase, or ALLINIs. ALLINIs promote IN aggregation by stabilizing an interaction between the catalytic core domain (CCD) and carboxy-terminal domain (CTD) that undermines viral particle formation in late replication. Ongoing challenges with inhibitor potency, toxicity, and viral resistance motivate research to understand their mechanism. Here, we report a 2.93 Å X-ray crystal structure of the minimal ternary complex between CCD_, CTD_, and the ALLINI BI-224436. This structure reveals an asymmetric ternary complex with a prominent network of π-mediated interactions that suggest specific avenues for future ALLINI development and optimization.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0012704

OSTI ID:: 2470320

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 3 Vol. 19; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

References (118)

Clustal Omega for making accurate alignments of many protein sequences: Clustal Omega for Many Protein Sequences Sievers, Fabian; Higgins, Desmond G. Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3290	journal	October 2017
UCSF ChimeraX : Structure visualization for researchers, educators, and developers Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Protein Science, Vol. 30, Issue 1 https://doi.org/10.1002/pro.3943	journal	October 2020
Solution structure of the His 12 → Cys mutant of the N-terminal zinc binding domain of HIV-1 integrase complexed to cadmium Cai, Mengli; Caffrey, Michael; Clore, G. Marius Protein Science, Vol. 7, Issue 12 https://doi.org/10.1002/pro.5560071221	journal	December 1998
Identification of cellular factors binding to acetylated HIV-1 integrase Allouch, Awatef; Cereseto, Anna Amino Acids, Vol. 41, Issue 5 https://doi.org/10.1007/s00726-009-0444-3	journal	December 2009
Integrase Strand Transfer Inhibitors in HIV Therapy Mesplède, Thibault; Wainberg, Mark A. Infectious Diseases and Therapy, Vol. 2, Issue 2 https://doi.org/10.1007/s40121-013-0020-8	journal	November 2013
HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots Schröder, Astrid R. W.; Shinn, Paul; Chen, Huaming Cell, Vol. 110, Issue 4 https://doi.org/10.1016/S0092-8674(02)00864-4	journal	August 2002
Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study Molina, Jean-Michel; LaMarca, Anthony; Andrade-Villanueva, Jaime The Lancet Infectious Diseases, Vol. 12, Issue 1 https://doi.org/10.1016/S1473-3099(11)70249-3	journal	January 2012
Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial Wijting, Ingeborg; Rokx, Casper; Boucher, Charles The Lancet HIV, Vol. 4, Issue 12 https://doi.org/10.1016/S2352-3018(17)30152-2	journal	December 2017
Calculations and Publication-Quality Illustrations for Analytical Ultracentrifugation Data Brautigam, Chad A. Methods in Enzymology https://doi.org/10.1016/bs.mie.2015.05.001	book	January 2015
Sedimentation equilibrium analysis of protein interactions with global implicit mass conservation constraints and systematic noise decomposition Vistica, Jennifer; Dam, Julie; Balbo, Andrea Analytical Biochemistry, Vol. 326, Issue 2 https://doi.org/10.1016/j.ab.2003.12.014	journal	March 2004
Indole-based allosteric inhibitors of HIV-1 integrase Patel, Pratiq A.; Kvaratskhelia, Nina; Mansour, Yara Bioorganic & Medicinal Chemistry Letters, Vol. 26, Issue 19 https://doi.org/10.1016/j.bmcl.2016.08.037	journal	October 2016
HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis Kessl, Jacques J.; Kutluay, Sebla B.; Townsend, Dana Cell, Vol. 166, Issue 5 https://doi.org/10.1016/j.cell.2016.07.044	journal	August 2016
The TRIM Family Protein KAP1 Inhibits HIV-1 Integration Allouch, Awatef; Di Primio, Cristina; Alpi, Emanuele Cell Host & Microbe, Vol. 9, Issue 6 https://doi.org/10.1016/j.chom.2011.05.004	journal	June 2011
Dynamic microtubules at the synapse Dent, Erik W. Current Opinion in Neurobiology, Vol. 63 https://doi.org/10.1016/j.conb.2020.01.003	journal	August 2020
Crystal structure of the HIV‐1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site Wielens, Jerome; Headey, Stephen J.; Jeevarajah, Dharshini FEBS Letters, Vol. 584, Issue 8 https://doi.org/10.1016/j.febslet.2010.03.016	journal	March 2010
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Retroviral intasomes arising Engelman, Alan N.; Cherepanov, Peter Current Opinion in Structural Biology, Vol. 47 https://doi.org/10.1016/j.sbi.2017.04.005	journal	December 2017
The Survival Motor Neuron Protein Forms Soluble Glycine Zipper Oligomers Martin, Renee; Gupta, Kushol; Ninan, Nisha S. Structure, Vol. 20, Issue 11 https://doi.org/10.1016/j.str.2012.08.024	journal	November 2012
Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions Gupta, Kushol; Allen, Audrey; Giraldo, Carolina Structure, Vol. 29, Issue 3 https://doi.org/10.1016/j.str.2020.12.001	journal	March 2021
Long-Acting Cabotegravir for HIV/AIDS Prophylaxis Engelman, Kathleen D.; Engelman, Alan N. Biochemistry, Vol. 60, Issue 22 https://doi.org/10.1021/acs.biochem.1c00157	journal	May 2021
Retroviral DNA Integration Lesbats, Paul; Engelman, Alan N.; Cherepanov, Peter Chemical Reviews, Vol. 116, Issue 20 https://doi.org/10.1021/acs.chemrev.6b00125	journal	May 2016
Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors Li, Guo; Meanwell, Nicholas A.; Krystal, Mark R. Journal of Medicinal Chemistry, Vol. 63, Issue 5 https://doi.org/10.1021/acs.jmedchem.9b01681	journal	February 2020
An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors Wilson, Tyler A.; Koneru, Pratibha C.; Rebensburg, Stephanie V. ACS Medicinal Chemistry Letters, Vol. 10, Issue 2 https://doi.org/10.1021/acsmedchemlett.8b00633	journal	January 2019
Solution Structure of the DNA Binding Domain of HIV-1 Integrase Lodi, Patricia J.; Ernst, James A.; Kuszewski, John Biochemistry, Vol. 34, Issue 31 https://doi.org/10.1021/bi00031a002	journal	August 1995
Oligomeric States of the HIV-1 Integrase As Measured by Time-Resolved Fluorescence Anisotropy ^† Deprez, Eric; Tauc, Patrick; Leh, Hervé Biochemistry, Vol. 39, Issue 31 https://doi.org/10.1021/bi000397j	journal	August 2000
Heteroaromatic Rings of the Future Pitt, William R.; Parry, David M.; Perry, Benjamin G. Journal of Medicinal Chemistry, Vol. 52, Issue 9 https://doi.org/10.1021/jm801513z	journal	April 2009
Molecular Recognition in Nicotinic Acetylcholine Receptors: The Importance of π−Cation Interactions Schmitt, Jeffrey D.; Sharples, Christopher G. V.; Caldwell, W. S. Journal of Medicinal Chemistry, Vol. 42, Issue 16 https://doi.org/10.1021/jm990093z	journal	July 1999
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1 Fader, Lee D.; Malenfant, Eric; Parisien, Mathieu ACS Medicinal Chemistry Letters, Vol. 5, Issue 4 https://doi.org/10.1021/ml500002n	journal	January 2014
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega Sievers, Fabian; Wilm, Andreas; Dineen, David Molecular Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1038/msb.2011.75	journal	January 2011
Acetylation regulates Cyclophilin A catalysis, immunosuppression and HIV isomerization Lammers, Michael; Neumann, Heinz; Chin, Jason W. Nature Chemical Biology, Vol. 6, Issue 5 https://doi.org/10.1038/nchembio.342	journal	April 2010
Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication Christ, Frauke; Voet, Arnout; Marchand, Arnaud Nature Chemical Biology, Vol. 6, Issue 6 https://doi.org/10.1038/nchembio.370	journal	May 2010
A role for LEDGF/p75 in targeting HIV DNA integration Ciuffi, Angela; Llano, Manuel; Poeschla, Eric Nature Medicine, Vol. 11, Issue 12 https://doi.org/10.1038/nm1329	journal	November 2005
Improved R-factors for diffraction data analysis in macromolecular crystallography Diederichs, Kay; Karplus, P. Andrew Nature Structural Biology, Vol. 4, Issue 4 https://doi.org/10.1038/nsb0497-269	journal	April 1997
Solution structure of the N-terminal zinc binding domain of HIV-1 integrase Cai, Mengli; Zheng, Ronglan; Caffrey, Michael Nature Structural Biology, Vol. 4, Issue 7 https://doi.org/10.1038/nsb0797-567	journal	July 1997
The DNA-binding domain of HIV-1 integrase has an SH3-like fold Eijkelenboom, Astrid P. A. M.; Puras Lutzke, Ramon A.; Boelens, Rolf Nature Structural & Molecular Biology, Vol. 2, Issue 9 https://doi.org/10.1038/nsb0995-807	journal	September 1995
Structure and function of retroviral integrase Maertens, Goedele N.; Engelman, Alan N.; Cherepanov, Peter Nature Reviews Microbiology, Vol. 20, Issue 1 https://doi.org/10.1038/s41579-021-00586-9	journal	July 2021
Acetylation of HIV-1 integrase by p300 regulates viral integration Cereseto, Anna; Manganaro, Lara; Gutierrez, Maria Ines The EMBO Journal, Vol. 24, Issue 17 https://doi.org/10.1038/sj.emboj.7600770	journal	August 2005
Cation–π interactions in protein–ligand binding: theory and data-mining reveal different roles for lysine and arginine Kumar, Kiran; Woo, Shin M.; Siu, Thomas Chemical Science, Vol. 9, Issue 10 https://doi.org/10.1039/C7SC04905F	journal	January 2018
Solution structure of the core SMN–Gemin2 complex Sarachan, Kathryn L.; Valentine, Kathleen G.; Gupta, Kushol Biochemical Journal, Vol. 445, Issue 3 https://doi.org/10.1042/BJ20120241	journal	July 2012
Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection Cooper, David A.; Steigbigel, Roy T.; Gatell, Jose M. New England Journal of Medicine, Vol. 359, Issue 4 https://doi.org/10.1056/NEJMoa0708978	journal	July 2008
HIV Drug Resistance Clavel, François; Hance, Allan J. New England Journal of Medicine, Vol. 350, Issue 10 https://doi.org/10.1056/NEJMra025195	journal	March 2004
Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75 Cherepanov, Peter; Ambrosio, Andre L. B.; Rahman, Shaila Proceedings of the National Academy of Sciences, Vol. 102, Issue 48 https://doi.org/10.1073/pnas.0506924102	journal	October 2005
Toward the structural genomics of complexes: Crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis Strong, M.; Sawaya, M. R.; Wang, S. Proceedings of the National Academy of Sciences, Vol. 103, Issue 21 https://doi.org/10.1073/pnas.0602606103	journal	May 2006
Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation Jurado, K. A.; Wang, H.; Slaughter, A. Proceedings of the National Academy of Sciences, Vol. 110, Issue 21 https://doi.org/10.1073/pnas.1300703110	journal	April 2013
Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding Chen, J. C. -H.; Krucinski, J.; Miercke, L. J. W. Proceedings of the National Academy of Sciences, Vol. 97, Issue 15 https://doi.org/10.1073/pnas.150220297	journal	July 2000
DNA binding induces dissociation of the multimeric form of HIV-1 integrase: A time-resolved fluorescence anisotropy study Deprez, E.; Tauc, P.; Leh, H. Proceedings of the National Academy of Sciences, Vol. 98, Issue 18 https://doi.org/10.1073/pnas.181024498	journal	August 2001
Three new structures of the core domain of HIV-1 integrase: An active site that binds magnesium Goldgur, Yehuda; Dyda, Fred; Hickman, Alison B. Proceedings of the National Academy of Sciences, Vol. 95, Issue 16 https://doi.org/10.1073/pnas.95.16.9150	journal	August 1998
Cation-pi interactions in structural biology Gallivan, J. P.; Dougherty, D. A. Proceedings of the National Academy of Sciences, Vol. 96, Issue 17 https://doi.org/10.1073/pnas.96.17.9459	journal	August 1999
A Soluble Active Mutant of HIV-1 Integrase: INVOLVEMENT OF BOTH THE CORE AND CARBOXYL-TERMINAL DOMAINS IN MULTIMERIZATION Jenkins, Timothy M.; Engelman, Alan; Ghirlando, Rodolfo Journal of Biological Chemistry, Vol. 271, Issue 13 https://doi.org/10.1074/jbc.271.13.7712	journal	March 1996
Affinities between the Binding Partners of the HIV-1 Integrase Dimer-Lens Epithelium-derived Growth Factor (IN Dimer-LEDGF) Complex Tsiang, Manuel; Jones, Gregg S.; Hung, Magdeleine Journal of Biological Chemistry, Vol. 284, Issue 48 https://doi.org/10.1074/jbc.M109.040121	journal	November 2009
Structural Properties of HIV Integrase·Lens Epithelium-derived Growth Factor Oligomers Gupta, Kushol; Diamond, Tracy; Hwang, Young Journal of Biological Chemistry, Vol. 285, Issue 26 https://doi.org/10.1074/jbc.M110.114413	journal	April 2010
New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action Tsiang, Manuel; Jones, Gregg S.; Niedziela-Majka, Anita Journal of Biological Chemistry, Vol. 287, Issue 25 https://doi.org/10.1074/jbc.M112.347534	journal	April 2012
Multimode, Cooperative Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors Kessl, Jacques J.; Jena, Nivedita; Koh, Yasuhiro Journal of Biological Chemistry, Vol. 287, Issue 20 https://doi.org/10.1074/jbc.M112.354373	journal	May 2012
Interaction of the HIV-1 Intasome with Transportin 3 Protein (TNPO3 or TRN-SR2) Larue, Ross; Gupta, Kushol; Wuensch, Christiane Journal of Biological Chemistry, Vol. 287, Issue 41 https://doi.org/10.1074/jbc.M112.384669	journal	October 2012
Identification of Residues in the C-terminal Domain of HIV-1 Integrase That Mediate Binding to the Transportin-SR2 Protein De Houwer, Stephanie; Demeulemeester, Jonas; Thys, Wannes Journal of Biological Chemistry, Vol. 287, Issue 41 https://doi.org/10.1074/jbc.M112.387944	journal	October 2012
The A128T Resistance Mutation Reveals Aberrant Protein Multimerization as the Primary Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors Feng, Lei; Sharma, Amit; Slaughter, Alison Journal of Biological Chemistry, Vol. 288, Issue 22 https://doi.org/10.1074/jbc.M112.443390	journal	April 2013
Allosteric Inhibition of Human Immunodeficiency Virus Integrase: LATE BLOCK DURING VIRAL REPLICATION AND ABNORMAL MULTIMERIZATION INVOLVING SPECIFIC PROTEIN DOMAINS Gupta, Kushol; Brady, Troy; Dyer, Benjamin M. Journal of Biological Chemistry, Vol. 289, Issue 30 https://doi.org/10.1074/jbc.M114.551119	journal	June 2014
A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase Shkriabai, Nikoloz; Dharmarajan, Venkatasubramanian; Slaughter, Alison Journal of Biological Chemistry, Vol. 289, Issue 38 https://doi.org/10.1074/jbc.M114.589572	journal	August 2014
Oligomeric Properties of Survival Motor Neuron·Gemin2 Complexes Gupta, Kushol; Martin, Renee; Sharp, Robert Journal of Biological Chemistry, Vol. 290, Issue 33 https://doi.org/10.1074/jbc.M115.667279	journal	August 2015
A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain Patel, Disha; Antwi, Janet; Koneru, Pratibha C. Journal of Biological Chemistry, Vol. 291, Issue 45 https://doi.org/10.1074/jbc.M116.753384	journal	November 2016
Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing Hoyte, Ashley C.; Jamin, Augusta V.; Koneru, Pratibha C. Journal of Biological Chemistry, Vol. 292, Issue 48 https://doi.org/10.1074/jbc.M117.816645	journal	December 2017
Dynamic Modulation of HIV-1 Integrase Structure and Function by Cellular Lens Epithelium-derived Growth Factor (LEDGF) Protein McKee, Christopher J.; Kessl, Jacques J.; Shkriabai, Nikolozi Journal of Biological Chemistry, Vol. 283, Issue 46 https://doi.org/10.1074/jbc.M805843200	journal	November 2008
Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition Engelman, Alan N. Journal of Biological Chemistry, Vol. 294, Issue 41 https://doi.org/10.1074/jbc.REV119.006901	journal	August 2019
Modulating Target Site Selection During Human Immunodeficiency Virus DNA Integration In Vitro with an Engineered Tethering Factor Ciuffi, Angela; Diamond, Tracy L.; Hwang, Young Human Gene Therapy, Vol. 17, Issue 9 https://doi.org/10.1089/hum.2006.17.960	journal	September 2006
AL2CO: calculation of positional conservation in a protein sequence alignment Pei, J.; Grishin, N. V. Bioinformatics, Vol. 17, Issue 8 https://doi.org/10.1093/bioinformatics/17.8.700	journal	August 2001
HIV-1 Tat transcriptional activity is regulated by acetylation Kiernan, R. E. The EMBO Journal, Vol. 18, Issue 21 https://doi.org/10.1093/emboj/18.21.6106	journal	November 1999
Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein Wang, J. -Y. The EMBO Journal, Vol. 20, Issue 24 https://doi.org/10.1093/emboj/20.24.7333	journal	December 2001
The S230R Integrase Substitution Associated With Virus Load Rebound During Dolutegravir Monotherapy Confers Low-Level Resistance to Integrase Strand-Transfer Inhibitors Pham, Hanh T.; Labrie, Lydia; Wijting, Ingeborg E. A. The Journal of Infectious Diseases, Vol. 218, Issue 5 https://doi.org/10.1093/infdis/jiy175	journal	March 2018
Role of metal ions in catalysis by HIV integrase analyzed using a quantitative PCR disintegration assay Diamond, Tracy L.; Bushman, Frederic D. Nucleic Acids Research, Vol. 34, Issue 21 https://doi.org/10.1093/nar/gkl862	journal	November 2006
HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor Wang, Hao; Jurado, Kellie A.; Wu, Xiaolin Nucleic Acids Research, Vol. 40, Issue 22 https://doi.org/10.1093/nar/gks913	journal	October 2012
The RING 2.0 web server for high quality residue interaction networks Piovesan, Damiano; Minervini, Giovanni; Tosatto, Silvio C. E. Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw315	journal	May 2016
CASTp 3.0: computed atlas of surface topography of proteins Tian, Wei; Chen, Chang; Lei, Xue Nucleic Acids Research, Vol. 46, Issue W1 https://doi.org/10.1093/nar/gky473	journal	June 2018
Human H4 tail stimulates HIV-1 integration through binding to the carboxy-terminal domain of integrase Mauro, Eric; Lesbats, Paul; Lapaillerie, Delphine Nucleic Acids Research, Vol. 47, Issue 7 https://doi.org/10.1093/nar/gkz091	journal	February 2019
We need to use the best antiretroviral drugs worldwide to prevent HIV drug resistance Brenner, Bluma; Wainberg, Mark A. AIDS, Vol. 30, Issue 17 https://doi.org/10.1097/QAD.0000000000001234	journal	November 2016
HIV DNA Integration Craigie, R.; Bushman, F. D. Cold Spring Harbor Perspectives in Medicine, Vol. 2, Issue 7 https://doi.org/10.1101/cshperspect.a006890	journal	May 2012
LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration Shun, M. -C.; Raghavendra, N. K.; Vandegraaff, N. Genes & Development, Vol. 21, Issue 14 https://doi.org/10.1101/gad.1565107	journal	July 2007
HIV integration site selection: Analysis by massively parallel pyrosequencing reveals association with epigenetic modifications Wang, G. P.; Ciuffi, A.; Leipzig, J. Genome Research, Vol. 17, Issue 8 https://doi.org/10.1101/gr.6286907	journal	July 2007
Global indicators of X-ray data quality Weiss, Manfred S. Journal of Applied Crystallography, Vol. 34, Issue 2 https://doi.org/10.1107/S0021889800018227	journal	April 2001
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Solving structures of protein complexes by molecular replacement with Phaser McCoy, Airlie J. Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 1 https://doi.org/10.1107/S0907444906045975	journal	December 2006
REFMAC 5 for the refinement of macromolecular crystal structures Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911001314	journal	March 2011
Deformable elastic network refinement for low-resolution macromolecular crystallography Schröder, Gunnar F.; Levitt, Michael; Brunger, Axel T. Acta Crystallographica Section D Biological Crystallography, Vol. 70, Issue 9 https://doi.org/10.1107/S1399004714016496	journal	August 2014
The PDB_REDO server for macromolecular structure model optimization Joosten, Robbie P.; Long, Fei; Murshudov, Garib N. IUCrJ, Vol. 1, Issue 4 https://doi.org/10.1107/S2052252514009324	journal	May 2014
NSLS-II MX beamlines FMX for micro-crystallography & AMX for highly automated MX Fuchs, Martin; Sweet, Robert; Berman, Lonny Acta Crystallographica Section A Foundations and Advances, Vol. 70, Issue a1 https://doi.org/10.1107/S2053273314082667	journal	August 2014
DIALS : implementation and evaluation of a new integration package Winter, Graeme; Waterman, David G.; Parkhurst, James M. Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 2 https://doi.org/10.1107/S2059798317017235	journal	February 2018
An Essential Role for LEDGF/p75 in HIV Integration Llano, M.; Saenz, D. T.; Meehan, A. Science, Vol. 314, Issue 5798 https://doi.org/10.1126/science.1132319	journal	October 2006
Inhibitors of Strand Transfer That Prevent Integration and Inhibit HIV-1 Replication in Cells Hazuda, Daria J.; Felock, Peter; Witmer, Marc Science, Vol. 287, Issue 5453 https://doi.org/10.1126/science.287.5453.646	journal	January 2000
Crystal Structure of the Catalytic Domain of HIV-1 Integrase: Similarity to Other Polynucleotidyl Transferases Dyda, Fred; Hickman, Alison B.; Jenkins, Timothy M. Science, Vol. 266, Issue 5193 https://doi.org/10.1126/science.7801124	journal	December 1994
Small-Molecule Inhibitors of the LEDGF/p75 Binding Site of Integrase Block HIV Replication and Modulate Integrase Multimerization Christ, Frauke; Shaw, Stephen; Demeulemeester, Jonas Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 8 https://doi.org/10.1128/AAC.00717-12	journal	June 2012
Mutations Associated with Failure of Raltegravir Treatment Affect Integrase Sensitivity to the Inhibitor In Vitro Malet, I.; Delelis, O.; Valantin, M. -A. Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 4 https://doi.org/10.1128/AAC.01228-07	journal	January 2008
Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor Fenwick, Craig; Amad, Ma'an; Bailey, Murray D. Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 6 https://doi.org/10.1128/AAC.02719-13	journal	March 2014
Broad Phenotypic Cross-Resistance to Elvitegravir in HIV-Infected Patients Failing on Raltegravir-Containing Regimens Garrido, Carolina; Villacian, Jorge; Zahonero, Natalia Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 6 https://doi.org/10.1128/AAC.06170-11	journal	June 2012
Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells Madison, Michaela K.; Lawson, Dana Q.; Elliott, Jennifer Journal of Virology, Vol. 91, Issue 17 https://doi.org/10.1128/JVI.00821-17	journal	September 2017
Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication Tekeste, Shewit S.; Wilkinson, Thomas A.; Weiner, Ethan M. Journal of Virology, Vol. 89, Issue 23 https://doi.org/10.1128/JVI.01471-15	journal	September 2015
Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation Fontana, Juan; Jurado, Kellie A.; Cheng, Naiqian Journal of Virology, Vol. 89, Issue 19 https://doi.org/10.1128/JVI.01522-15	journal	July 2015
Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137) Shimura, Kazuya; Kodama, Eiichi; Sakagami, Yasuko Journal of Virology, Vol. 82, Issue 2 https://doi.org/10.1128/JVI.01534-07	journal	October 2007
Genetic Analyses of Conserved Residues in the Carboxyl-Terminal Domain of Human Immunodeficiency Virus Type 1 Integrase Lu, Richard; Ghory, Hina Z.; Engelman, Alan Journal of Virology, Vol. 79, Issue 16 https://doi.org/10.1128/JVI.79.16.10356-10368.2005	journal	August 2005
Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro Engelman, A.; Craigie, R. Journal of Virology, Vol. 66, Issue 11 https://doi.org/10.1128/jvi.66.11.6361-6369.1992	journal	November 1992
Biochemical and virological analysis of the 18-residue C-terminal tail of HIV-1 integrase Dar, Mohd J.; Monel, Blandine; Krishnan, Lavanya Retrovirology, Vol. 6, Issue 1 https://doi.org/10.1186/1742-4690-6-94	journal	October 2009
HIV-1 IN/Pol recruits LEDGF/p75 into viral particles Desimmie, Belete Ayele; Weydert, Caroline; Schrijvers, Rik Retrovirology, Vol. 12, Issue 1 https://doi.org/10.1186/s12977-014-0134-4	journal	February 2015
Influence of the amino-terminal sequence on the structure and function of HIV integrase Eilers, Grant; Gupta, Kushol; Allen, Audrey Retrovirology, Vol. 17, Issue 1 https://doi.org/10.1186/s12977-020-00537-x	journal	August 2020
Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase Gupta, Kushol; Turkki, Vesa; Sherrill-Mix, Scott PLOS Biology, Vol. 14, Issue 12 https://doi.org/10.1371/journal.pbio.1002584	journal	December 2016
Selective Histonedeacetylase Inhibitor M344 Intervenes in HIV-1 Latency through Increasing Histone Acetylation and Activation of NF-kappaB Ying, Hao; Zhang, Yuhao; Zhou, Xin PLoS ONE, Vol. 7, Issue 11 https://doi.org/10.1371/journal.pone.0048832	journal	November 2012
Non-Catalytic Site HIV-1 Integrase Inhibitors Disrupt Core Maturation and Induce a Reverse Transcription Block in Target Cells Balakrishnan, Mini; Yant, Stephen R.; Tsai, Luong PLoS ONE, Vol. 8, Issue 9 https://doi.org/10.1371/journal.pone.0074163	journal	September 2013
The Effect of Macromolecular Crowding on the Electrostatic Component of Barnase–Barstar Binding: A Computational, Implicit Solvent-Based Study Qi, Helena W.; Nakka, Priyanka; Chen, Connie PLoS ONE, Vol. 9, Issue 6 https://doi.org/10.1371/journal.pone.0098618	journal	June 2014
Therapy-Emergent Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Patients: A Subgroup Meta-Analysis of Clinical Trials You, Jiangzhou; Wang, Hongren; Huang, Xiaojun PLOS ONE, Vol. 11, Issue 8 https://doi.org/10.1371/journal.pone.0160087	journal	August 2016
A Novel Co-Crystal Structure Affords the Design of Gain-of-Function Lentiviral Integrase Mutants in the Presence of Modified PSIP1/LEDGF/p75 Hare, Stephen; Shun, Ming-Chieh; Gupta, Saumya Shree PLoS Pathogens, Vol. 5, Issue 1 https://doi.org/10.1371/journal.ppat.1000259	journal	January 2009
Structural Basis for Functional Tetramerization of Lentiviral Integrase Hare, Stephen; Di Nunzio, Francesca; Labeja, Alfred PLoS Pathogens, Vol. 5, Issue 7 https://doi.org/10.1371/journal.ppat.1000515	journal	July 2009
A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase Sharma, Amit; Slaughter, Alison; Jena, Nivedita PLoS Pathogens, Vol. 10, Issue 5 https://doi.org/10.1371/journal.ppat.1004171	journal	May 2014
Mutations altering acetylated residues in the CTD of HIV-1 integrase cause defects in proviral transcription at early times after integration of viral DNA Winans, Shelby; Goff, Stephen P. PLOS Pathogens, Vol. 16, Issue 12 https://doi.org/10.1371/journal.ppat.1009147	journal	December 2020
A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site Maehigashi, Tatsuya; Ahn, Seohyun; Kim, Uk-Il PLOS Pathogens, Vol. 17, Issue 7 https://doi.org/10.1371/journal.ppat.1009671	journal	July 2021
Structure and Function of HIV-1 Integrase Chiu, Thang; Davies, David Current Topics in Medicinal Chemistry, Vol. 4, Issue 9 https://doi.org/10.2174/1568026043388547	journal	May 2004
Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis Elliott, Jennifer L.; Kutluay, Sebla B. Viruses, Vol. 12, Issue 9 https://doi.org/10.3390/v12091005	journal	September 2020
Resistance against Integrase Strand Transfer Inhibitors and Relevance to HIV Persistence Mesplède, Thibault; Wainberg, Mark Viruses, Vol. 7, Issue 7 https://doi.org/10.3390/v7072790	journal	July 2015
Influence of the amino-terminal sequence on the structure and function of HIV integrase Eilers, Grant; Gupta, Kushol; Allen, Audrey figshare https://doi.org/10.6084/m9.figshare.c.5108308.v1	collection	January 2020
HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors Koneru, Pratibha C.; Francis, Ashwanth C.; Deng, Nanjie eLife, Vol. 8 https://doi.org/10.7554/eLife.46344	journal	May 2019
Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis Elliott, Jennifer L.; Eschbach, Jenna E.; Koneru, Pratibha C. eLife, Vol. 9 https://doi.org/10.7554/eLife.54311	journal	September 2020

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60 APPLIED LIFE SCIENCES
HIV
HIV-1
crystal structure
dimers
drug interactions
electron density
molecular structure
protein structure

Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization

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