A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity

Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia; Osipiuk, Jerzy; Gu, Minyi; Zhang, Minjia; Mandapati, Kavitha; Gollapalli, Deviprasad R.; Gorla, Suresh Kumar; Hedstrom, Lizbeth; Joachimiak, Andrzej

doi:10.1074/jbc.M114.619767

Title: A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity

Journal Article · Fri Jan 09 00:00:00 EST 2015 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M114.619767· OSTI ID:1225229

Makowska-Grzyska, Magdalena ^[1]; Kim, Youngchang ^[1]; Maltseva, Natalia ^[1]; Osipiuk, Jerzy ^[2]; Gu, Minyi ^[1]; Zhang, Minjia ^[3]; Mandapati, Kavitha ^[3]; Gollapalli, Deviprasad R. ^[3]; Gorla, Suresh Kumar ^[3]; Hedstrom, Lizbeth ^[3]; Joachimiak, Andrzej ^[2]

Univ. of Chicago, Chicago, IL (United States)
Univ. of Chicago, Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
Brandeis Univ., Waltham, MA (United States)

The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5'-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD⁺, which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD⁺ and XMP/NAD⁺. In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD+ adenosine moiety. More importantly, this new NAD⁺-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD⁺-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. As a result, these findings offer a potential strategy for further ligand optimization.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02–06CH11357; HHSN272200700058C; HHSN272201200026C

OSTI ID:: 1225229

Journal Information:: Journal of Biological Chemistry, Vol. 290, Issue 9; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 30 works

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References (49)

Antibiotics for Emerging Pathogens Fischbach, M. A.; Walsh, C. T. Science, Vol. 325, Issue 5944 https://doi.org/10.1126/science.1176667	journal	August 2009
Structure of Apo- and Monometalated Forms of NDM-1—A Highly Potent Carbapenem-Hydrolyzing Metallo-β-Lactamase Kim, Youngchang; Tesar, Christine; Mire, Joseph PLoS ONE, Vol. 6, Issue 9 https://doi.org/10.1371/journal.pone.0024621	journal	September 2011
The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors Hedstrom, L.; Liechti, G.; B. Goldberg, J. Current Medicinal Chemistry, Vol. 18, Issue 13 https://doi.org/10.2174/092986711795590129	journal	May 2011
Structural Determinants of Inhibitor Selectivity in Prokaryotic IMP Dehydrogenases Gollapalli, Deviprasad R.; MacPherson, Iain S.; Liechti, George Chemistry & Biology, Vol. 17, Issue 10 https://doi.org/10.1016/j.chembiol.2010.07.014	journal	October 2010
Triazole-Linked Inhibitors of Inosine Monophosphate Dehydrogenase from Human and Mycobacterium tuberculosis Chen, Liqiang; Wilson, Daniel J.; Xu, Yanli Journal of Medicinal Chemistry, Vol. 53, Issue 12 https://doi.org/10.1021/jm100424m	journal	June 2010
Identification of Novel Mt-Guab2 Inhibitor Series Active against M. tuberculosis Usha, Veeraraghavan; Hobrath, Judith V.; Gurcha, Sudagar S. PLoS ONE, Vol. 7, Issue 3 https://doi.org/10.1371/journal.pone.0033886	journal	March 2012
Repurposing Cryptosporidium Inosine 5′-Monophosphate Dehydrogenase Inhibitors as Potential Antibacterial Agents Mandapati, Kavitha; Gorla, Suresh Kumar; House, Amanda L. ACS Medicinal Chemistry Letters, Vol. 5, Issue 8 https://doi.org/10.1021/ml500203p	journal	June 2014
IMP Dehydrogenase: Structure, Mechanism, and Inhibition Hedstrom, Lizbeth Chemical Reviews, Vol. 109, Issue 7 https://doi.org/10.1021/cr900021w	journal	July 2009
Bacillus anthracis Inosine 5′-Monophosphate Dehydrogenase in Action: The First Bacterial Series of Structures of Phosphate Ion-, Substrate-, and Product-Bound Complexes Makowska-Grzyska, Magdalena; Kim, Youngchang; Wu, Ruiying Biochemistry, Vol. 51, Issue 31 https://doi.org/10.1021/bi300511w	journal	July 2012
The TIM-barrel fold: a versatile framework for efficient enzymes Wierenga, R. K. FEBS Letters, Vol. 492, Issue 3 https://doi.org/10.1016/S0014-5793(01)02236-0	journal	March 2001
The structure of a domain common to archaebacteria and the homocystinuria disease protein Bateman, Alex Trends in Biochemical Sciences, Vol. 22, Issue 1 https://doi.org/10.1016/S0968-0004(96)30046-7	journal	January 1997
Characteristics and Crystal Structure of Bacterial Inosine-5‘-monophosphate Dehydrogenase ^† ^, ^‡ Zhang, Rong-guang; Evans, Gwyndaf; Rotella, Frank J. Biochemistry, Vol. 38, Issue 15 https://doi.org/10.1021/bi982858v	journal	April 1999
The Immunosuppressive Agent Mizoribine Monophosphate Forms a Transition State Analogue Complex with Inosine Monophosphate Dehydrogenase ^† Gan, Lu; Seyedsayamdost, Mohammad R.; Shuto, Satoshi Biochemistry, Vol. 42, Issue 4 https://doi.org/10.1021/bi0271401	journal	February 2003
Biochemical Analysis of the Modular Enzyme Inosine 5′-Monophosphate Dehydrogenase Nimmesgern, Elmar; Black, James; Futer, Olga Protein Expression and Purification, Vol. 17, Issue 2 https://doi.org/10.1006/prep.1999.1136	journal	November 1999
The CBS subdomain of inosine 5′-monophosphate dehydrogenase regulates purine nucleotide turnover: CBS subdomain of IMPDH Pimkin, Maxim; Markham, George D. Molecular Microbiology, Vol. 68, Issue 2 https://doi.org/10.1111/j.1365-2958.2008.06153.x	journal	February 2008
Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design Colby, T. D.; Vanderveen, K.; Strickler, M. D. Proceedings of the National Academy of Sciences, Vol. 96, Issue 7 https://doi.org/10.1073/pnas.96.7.3531	journal	March 1999
Crystal Structure of a Ternary Complex of Tritrichomonas foetus Inosine 5‘-Monophosphate Dehydrogenase: NAD ⁺ Orients the Active Site Loop for Catalysis ^† ^, ^‡ Gan, Lu; Petsko, Gregory A.; Hedstrom, Lizbeth Biochemistry, Vol. 41, Issue 44 https://doi.org/10.1021/bi0203785	journal	November 2002
Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain Felczak, Krzysztof; Chen, Liqiang; Wilson, Daniel Bioorganic & Medicinal Chemistry, Vol. 19, Issue 5 https://doi.org/10.1016/j.bmc.2011.01.042	journal	March 2011
Inosine Monophosphate Dehydrogenase and Its Inhibitors: An Overview Pankiewicz, Krzysztof W.; Goldstein, Barry M. ACS Symposium Series https://doi.org/10.1021/bk-2003-0839.ch001	book	March 2003
Targeting a Prokaryotic Protein in a Eukaryotic Pathogen: Identification of Lead Compounds against Cryptosporidiosis Umejiego, Nwakaso N.; Gollapalli, Deviprasad; Sharling, Lisa Chemistry & Biology, Vol. 15, Issue 1 https://doi.org/10.1016/j.chembiol.2007.12.010	journal	January 2008
A Screening Pipeline for Antiparasitic Agents Targeting Cryptosporidium Inosine Monophosphate Dehydrogenase Sharling, Lisa; Liu, Xiaoping; Gollapalli, Deviprasad R. PLoS Neglected Tropical Diseases, Vol. 4, Issue 8 https://doi.org/10.1371/journal.pntd.0000794	journal	August 2010
Triazole Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase Maurya, Sushil K.; Gollapalli, Deviprasad R.; Kirubakaran, Shivapriya Journal of Medicinal Chemistry, Vol. 52, Issue 15 https://doi.org/10.1021/jm900410u	journal	August 2009
Structure–activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Sharling, Lisa Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 5 https://doi.org/10.1016/j.bmcl.2012.01.029	journal	March 2012
Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia Journal of Medicinal Chemistry, Vol. 56, Issue 10 https://doi.org/10.1021/jm400241j	journal	May 2013
Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum Johnson, Corey R.; Gorla, Suresh Kumar; Kavitha, Mandapati Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 4 https://doi.org/10.1016/j.bmcl.2012.12.037	journal	February 2013
Selective and Potent Urea Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia Journal of Medicinal Chemistry, Vol. 55, Issue 17 https://doi.org/10.1021/jm3007917	journal	September 2012
The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity MacPherson, Iain S.; Kirubakaran, Sivapriya; Gorla, Suresh Kumar Journal of the American Chemical Society, Vol. 132, Issue 4 https://doi.org/10.1021/ja909947a	journal	February 2010
Integration of PCR Fragments at Any Specific Site within Cloning Vectors without the Use of Restriction Enzymes and DNA Ligase Geiser, Martin; Cébe, Régis; Drewello, Delia BioTechniques, Vol. 31, Issue 1 https://doi.org/10.2144/01311st05	journal	July 2001
High-throughput protein purification and quality assessment for crystallization Kim, Youngchang; Babnigg, Gyorgy; Jedrzejczak, Robert Methods, Vol. 55, Issue 1 https://doi.org/10.1016/j.ymeth.2011.07.010	journal	September 2011
The Structural Biology Center 19ID undulator beamline: facility specifications and protein crystallographic results Rosenbaum, Gerd; Alkire, Randy W.; Evans, Gwyndaf Journal of Synchrotron Radiation, Vol. 13, Issue 1 https://doi.org/10.1107/S0909049505036721	journal	December 2005
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes Minor, Wladek; Cymborowski, Marcin; Otwinowski, Zbyszek Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8 https://doi.org/10.1107/S0907444906019949	journal	July 2006
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
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
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Use of TLS parameters to model anisotropic displacements in macromolecular refinement Winn, M. D.; Isupov, M. N.; Murshudov, G. N. Acta Crystallographica Section D Biological Crystallography, Vol. 57, Issue 1 https://doi.org/10.1107/S0907444900014736	journal	January 2001
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids Davis, I. W.; Leaver-Fay, A.; Chen, V. B. Nucleic Acids Research, Vol. 35, Issue Web Server https://doi.org/10.1093/nar/gkm216	journal	May 2007
Asp338 Controls Hydride Transfer in Escherichia coli IMP Dehydrogenase ^† Kerr, Kathleen M.; Digits, Jennifer A.; Kuperwasser, Nicolas Biochemistry, Vol. 39, Issue 32 https://doi.org/10.1021/bi0005409	journal	August 2000
The photochemistry of the N-oxide function Albini, Angelo; Alpegiani, Marco Chemical Reviews, Vol. 84, Issue 1 https://doi.org/10.1021/cr00059a004	journal	February 1984
Purine N-Oxides. XII. Photochemical Changes Induced by Ultraviolet Radiation ^* Brown, George Bosworth; Levin, Gershon; Murphy, Sarah Biochemistry, Vol. 3, Issue 7 https://doi.org/10.1021/bi00895a002	journal	July 1964
Allosteric Activation via Kinetic Control: Potassium Accelerates a Conformational Change in IMP Dehydrogenase Riera, Thomas V.; Zheng, Lianqing; Josephine, Helen R. Biochemistry, Vol. 50, Issue 39 https://doi.org/10.1021/bi200785s	journal	October 2011
Imidazole-2-Thiones: Synthesis, Structure, Properties Trzhtsinskaya, Bella V.; Abramova, Nina D. Sulfur reports, Vol. 10, Issue 4 https://doi.org/10.1080/01961779108048760	journal	June 1991
2 Evolutionary and Structural Relationships among Dehydrogenases Rossman, Michael G.; Liljas, Anders; Brändén, Carl-Ivar The Enzymes https://doi.org/10.1016/S1874-6047(08)60210-3	book	January 1975
Unusual conformation of nicotinamide adenine dinucleotide (NAD) bound to diphtheria toxin: A comparison with NAD bound to the oxidoreductase enzymes Bell, Charles E.; Yeates, Todd O.; Eisenberg, David Protein Science, Vol. 6, Issue 10 https://doi.org/10.1002/pro.5560061004	journal	October 1997
Linking Distinct Conformations of Nicotinamide Adenine Dinucleotide with Protein Fold/Function Kuppuraj, Gopi; Sargsyan, Karen; Hua, Yun-Hao The Journal of Physical Chemistry B, Vol. 115, Issue 24 https://doi.org/10.1021/jp1118663	journal	June 2011
Cofactor mobility determines reaction outcome in the IMPDH and GMPR (β-α)8 barrel enzymes Patton, Gregory C.; Stenmark, Pål; Gollapalli, Deviprasad R. Nature Chemical Biology, Vol. 7, Issue 12 https://doi.org/10.1038/nchembio.693	journal	October 2011
Pharmacophore Binding Motifs for Nicotinamide Adenine Dinucleotide Analogues Across Multiple Protein Families: A Detailed Contact-Based Analysis of the Interaction between Proteins and NAD(P) Cofactors Giangreco, Ilenia; Packer, Martin J. Journal of Medicinal Chemistry, Vol. 56, Issue 15 https://doi.org/10.1021/jm400644z	journal	July 2013
Multiple sequence alignment with hierarchical clustering Corpet, F. Nucleic Acids Research, Vol. 16, Issue 22, p. 10881-10890 https://doi.org/10.1093/nar/16.22.10881	journal	November 1988
Deciphering key features in protein structures with the new ENDscript server Robert, Xavier; Gouet, Patrice Nucleic Acids Research, Vol. 42, Issue W1 https://doi.org/10.1093/nar/gku316	journal	April 2014

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60 APPLIED LIFE SCIENCES
antibiotic resistance
enzyme inhibitor
ligand-binding protein
microbial pathogenesis
nicotinamide adenine dinucleotide (NAD)
cryptosporidium parvum-selective inhibitors
antibacterial
cofactor-binding site
inosine 5'-monophosphate dehydrogenase

Title: A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity

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References (49)

Cited By (3)

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