Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

Begley, Darren W.; Edwards, Thomas E.; Raymond, Amy C.; Smith, Eric R.; Hartley, Robert C.; Abendroth, Jan; Sankaran, Banumathi; Lorimer, Donald D.; Myler, Peter J.; Staker, Bart L.; Stewart, Lance J.

doi:10.1107/s1744309111029009

Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

Journal Article · Tue Aug 16 00:00:00 EDT 2011 · Acta Crystallographica. Section F

DOI:https://doi.org/10.1107/s1744309111029009· OSTI ID:1625813

Begley, Darren W. ^[1]; Edwards, Thomas E. ^[2]; Raymond, Amy C. ^[2]; Smith, Eric R. ^[2]; Hartley, Robert C. ^[2]; Abendroth, Jan ^[2]; Sankaran, Banumathi ^[3]; Lorimer, Donald D. ^[2]; Myler, Peter J. ^[4]; Staker, Bart L. ^[2]; Stewart, Lance J. ^[2]

Seattle Structural Genomics Center for Infectious Disease, Seattle, WA (United States); Emerald BioStructures Inc., Bainbridge Island, WA (United States); DOE/OSTI
Seattle Structural Genomics Center for Infectious Disease, Seattle, WA (United States); Emerald BioStructures Inc., Bainbridge Island, WA (United States)
Berkeley Center for Structural Biology, Berkeley, CA (United States)
Seattle Structural Genomics Center for Infectious Disease, Seattle, WA (United States); Seattle BioMed, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States). School of Medicine. Depts. of Global Health, Medical Education and Biomedical Informatics

Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductasethymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625813

Journal Information:: Acta Crystallographica. Section F, Journal Name: Acta Crystallographica. Section F Journal Issue: 9 Vol. 67; ISSN ACSFCL; ISSN 1744-3091

Publisher:: International Union of CrystallographyCopyright Statement

Country of Publication:: United States

Language:: English

References (49)

Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases Sayre, Peter H.; Finer-Moore, Janet S.; Fritz, Timothy A. Journal of Molecular Biology, Vol. 313, Issue 4 https://doi.org/10.1006/jmbi.2001.5074	journal	November 2001
The Polymerase Incomplete Primer Extension (PIPE) Method Applied to High-Throughput Cloning and Site-Directed Mutagenesis Klock, Heath E.; Lesley, Scott A. Methods in Molecular Biology https://doi.org/10.1007/978-1-59745-196-3_6	book	January 2009
Thymidylate synthase: A target for anticancer drug design Harrap, K. R.; Jackman, A. L.; Newell, D. R. Advances in Enzyme Regulation, Vol. 29 https://doi.org/10.1016/0065-2571(89)90099-X	journal	January 1989
Conversion of Uracil Deoxyriboside to Thymidine of Deoxyribonucleic acid Friedkin, Morris; Roberts, DeWayne Journal of Biological Chemistry, Vol. 220, Issue 2 https://doi.org/10.1016/S0021-9258(18)65290-1	journal	June 1956
[45] Thymidine kinase from Escherichia coli Chen, Ming S.; Prusoff, William H. Methods in Enzymology https://doi.org/10.1016/S0076-6879(78)51047-1	book	January 1978
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Ulp1-SUMO Crystal Structure and Genetic Analysis Reveal Conserved Interactions and a Regulatory Element Essential for Cell Growth in Yeast Mossessova, Elena; Lima, Christopher D. Molecular Cell, Vol. 5, Issue 5 https://doi.org/10.1016/S1097-2765(00)80326-3	journal	May 2000
Babesiosis: Recent insights into an ancient disease Hunfeld, K.; Hildebrandt, A.; Gray, J. International Journal for Parasitology, Vol. 38, Issue 11 https://doi.org/10.1016/j.ijpara.2008.03.001	journal	September 2008
Babesiosis of cattle Bock, R.; Jackson, L.; De Vos, A. Parasitology, Vol. 129, Issue S1 https://doi.org/10.1017/S0031182004005190	journal	October 2004
Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors Yuthavong, Y.; Yuvaniyama, J.; Chitnumsub, P. Parasitology, Vol. 130, Issue 3 https://doi.org/10.1017/S003118200400664X	journal	January 1999
Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site Schiffer, Celia A.; Clifton, Ian J.; Davisson, V. Jo Biochemistry, Vol. 34, Issue 50 https://doi.org/10.1021/bi00050a007	journal	December 1995
Human Thymidylate Synthase Is in the Closed Conformation When Complexed with dUMP and Raltitrexed, an Antifolate Drug ^† ^, ^‡ Phan, Jason; Koli, Sangita; Minor, Wladek Biochemistry, Vol. 40, Issue 7 https://doi.org/10.1021/bi002413i	journal	February 2001
Lessons and Conclusions from Dissecting the Mechanism of a Bisubstrate Enzyme: Thymidylate Synthase Mutagenesis, Function, and Structure ^† Finer-Moore, Janet S.; Santi, Daniel V.; Stroud, Robert M. Biochemistry, Vol. 42, Issue 2 https://doi.org/10.1021/bi020599a	journal	January 2003
Nonconserved Residues Ala287 and Ser290 of the Cryptosporidium hominis Thymidylate Synthase Domain Facilitate Its Rapid Rate of Catalysis ^† ^, ^‡ Doan, Lanxuan T.; Martucci, W. Edward; Vargo, Melissa A. Biochemistry, Vol. 46, Issue 28 https://doi.org/10.1021/bi700531r	journal	July 2007
DNA and RNA Synthesis: Antifolates Kompis, Ivan M.; Islam, Khalid; Then, Rudolf L. Chemical Reviews, Vol. 105, Issue 2 https://doi.org/10.1021/cr0301144	journal	February 2005
A dideazatetrahydrofolate analog lacking a chiral center at C-6: N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl[benzoyl]-L-glutamic acid is an inhibitor of thymidylate synthase Taylor, Edward C.; Kuhnt, Dietmar; Shih, Chuan Journal of Medicinal Chemistry, Vol. 35, Issue 23 https://doi.org/10.1021/jm00101a023	journal	November 1992
Synthesis of N -{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3 H - pyrrolo[2,3- d ]pyrimidin-6-yl)thio]benzoyl}- l -glutamic Acid and N -{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3 H -pyrrolo[2,3- d ]pyrimidin- 6-yl)thio]benzoyl}- l -glutamic Acid as Dual Inhibitors of Dihydrofolate Reductase and Thymidylate Synthase and as Potential Antitumor Agents Gangjee, Aleem; Lin, Xin; Kisliuk, Roy L. Journal of Medicinal Chemistry, Vol. 48, Issue 23 https://doi.org/10.1021/jm058234m	journal	November 2005
Potent Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors: Classical and Nonclassical 2-Amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3- d ]pyrimidine Antifolates Gangjee, Aleem; Qiu, Yibin; Li, Wei Journal of Medicinal Chemistry, Vol. 51, Issue 18 https://doi.org/10.1021/jm8006933	journal	September 2008
A proteomic view of the Plasmodium falciparum life cycle Florens, Laurence; Washburn, Michael P.; Raine, J. Dale Nature, Vol. 419, Issue 6906, p. 520-526 https://doi.org/10.1038/nature01107	journal	October 2002
Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7 Langer, Gerrit; Cohen, Serge X.; Lamzin, Victor S. Nature Protocols, Vol. 3, Issue 7 https://doi.org/10.1038/nprot.2008.91	journal	June 2008
Structure of and kinetic channelling in bifunctional dihydrofolate reductase–thymidylate synthase Knighton, Daniel R.; Kan, Chen-Chen; Howland, Eleanor Nature Structural Biology, Vol. 1, Issue 3 https://doi.org/10.1038/nsb0394-186	journal	March 1994
Announcing the worldwide Protein Data Bank Berman, Helen; Henrick, Kim; Nakamura, Haruki Nature Structural & Molecular Biology, Vol. 10, Issue 12 https://doi.org/10.1038/nsb1203-980	journal	December 2003
Insights into antifolate resistance from malarial DHFR-TS structures Yuvaniyama, Jirundon; Chitnumsub, Penchit; Kamchonwongpaisan, Sumalee Nature Structural & Molecular Biology, Vol. 10, Issue 5 https://doi.org/10.1038/nsb921	journal	April 2003
Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Peterson, D. S.; Walliker, D.; Wellems, T. E. Proceedings of the National Academy of Sciences, Vol. 85, Issue 23 https://doi.org/10.1073/pnas.85.23.9114	journal	December 1988
Escherichia coli thymidylate synthase: amino acid substitutions by suppression of amber nonsense mutations. Michaels, M. L.; Kim, C. W.; Matthews, D. A. Proceedings of the National Academy of Sciences, Vol. 87, Issue 10 https://doi.org/10.1073/pnas.87.10.3957	journal	May 1990
Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Foote, S. J.; Galatis, D.; Cowman, A. F. Proceedings of the National Academy of Sciences, Vol. 87, Issue 8 https://doi.org/10.1073/pnas.87.8.3014	journal	April 1990
Phylogenetic Classification of Protozoa Based on the Structure of the Linker Domain in the Bifunctional Enzyme, Dihydrofolate Reductase-Thymidylate Synthase O'Neil, Robert H.; Lilien, Ryan H.; Donald, Bruce R. Journal of Biological Chemistry, Vol. 278, Issue 52 https://doi.org/10.1074/jbc.M310328200	journal	October 2003
Kinetic Characterization of Bifunctional Thymidylate Synthase-Dihydrofolate Reductase (TS-DHFR) from Cryptosporidium hominis : A PARADIGM SHIFT FOR TS ACTIVITY AND CHANNELING BEHAVIOR Atreya, Chloé E.; Anderson, Karen S. Journal of Biological Chemistry, Vol. 279, Issue 18 https://doi.org/10.1074/jbc.M400009200	journal	February 2004
Ticks and Tickborne Bacterial Diseases in Humans: An Emerging Infectious Threat Parola, P.; Raoult, D. Clinical Infectious Diseases, Vol. 32, Issue 6 https://doi.org/10.1086/319347	journal	March 2001
Emergence of Resistance to Azithromycin‐Atovaquone in Immunocompromised Patients with Babesia microti Infection Wormser, Gary P.; Prasad, Aakanksha; Neuhaus, Ellen Clinical Infectious Diseases, Vol. 50, Issue 3 https://doi.org/10.1086/649859	journal	February 2010
Clustal W and Clustal X version 2.0 Larkin, M. A.; Blackshields, G.; Brown, N. P. Bioinformatics, Vol. 23, Issue 21, p. 2947-2948 https://doi.org/10.1093/bioinformatics/btm404	journal	September 2007
The Protein Data Bank Berman, H. M. Nucleic Acids Research, Vol. 28, Issue 1 https://doi.org/10.1093/nar/28.1.235	journal	January 2000
Folate-based thymidylate synthase inhibitors as anticancer drugs Jackman, A. L.; Calvert, A. H. Annals of Oncology, Vol. 6, Issue 9 https://doi.org/10.1093/oxfordjournals.annonc.a059353	journal	November 1995
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
Nanovolume optimization of protein crystal growth using the microcapillary protein crystallization system Gerdts, Cory J.; Stahl, Glenn L.; Napuli, Alberto Journal of Applied Crystallography, Vol. 43, Issue 5 https://doi.org/10.1107/S0021889810027378	journal	August 2010
Automatic indexing of rotation diffraction patterns Kabsch, W. Journal of Applied Crystallography, Vol. 21, Issue 1 https://doi.org/10.1107/S0021889887009737	journal	February 1988
Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants Kabsch, W. Journal of Applied Crystallography, Vol. 26, Issue 6 https://doi.org/10.1107/S0021889893005588	journal	December 1993
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
The plug-based nanovolume Microcapillary Protein Crystallization System (MPCS) Gerdts, Cory J.; Elliott, Mark; Lovell, Scott Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 11 https://doi.org/10.1107/S0907444908028060	journal	October 2008
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
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
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
Salvage and storage of infectious disease protein targets in the SSGCID high-throughput crystallization pathway using microfluidics Christensen, Jeff; Gerdts, Cory J.; Clifton, Mathew C. Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 67, Issue 9 https://doi.org/10.1107/S1744309111023232	journal	August 2011
The Protein Maker: an automated system for high-throughput parallel purification Smith, Eric R.; Begley, Darren W.; Anderson, Vanessa Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 67, Issue 9 https://doi.org/10.1107/S1744309111028776	journal	August 2011
Babesiosis Homer, M. J.; Aguilar-Delfin, I.; Telford, S. R. Clinical Microbiology Reviews, Vol. 13, Issue 3 https://doi.org/10.1128/CMR.13.3.451-469.2000	journal	July 2000
The Catalytic Mechanism and Structure of Thymidylate Synthase Carreras, Christopher W.; Santi, Daniel V. Annual Review of Biochemistry, Vol. 64, Issue 1 https://doi.org/10.1146/annurev.bi.64.070195.003445	journal	June 1995
Genome Sequence of Babesia bovis and Comparative Analysis of Apicomplexan Hemoprotozoa Brayton, Kelly A.; Lau, Audrey O. T.; Herndon, David R. PLoS Pathogens, Vol. 3, Issue 10 https://doi.org/10.1371/journal.ppat.0030148	journal	October 2007
Thymidylate Synthase Structure, Function and Implication in Drug Discovery Costi, M.; Ferrari, S.; Venturelli, A. Current Medicinal Chemistry, Vol. 12, Issue 19 https://doi.org/10.2174/0929867054864868	journal	September 2005

Cited By (7)

Screening the Medicines for Malaria Venture Pathogen Box against piroplasm parasites Nugraha, Arifin Budiman; Tuvshintulga, Bumduuren; Guswanto, Azirwan International Journal for Parasitology: Drugs and Drug Resistance, Vol. 10 https://doi.org/10.1016/j.ijpddr.2019.06.004	journal	August 2019
Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome Baugh, Loren; Gallagher, Larry A.; Patrapuvich, Rapatbhorn PLoS ONE, Vol. 8, Issue 1 https://doi.org/10.1371/journal.pone.0053851	journal	January 2013
Human dihydrofolate reductase and thymidylate synthase form a complex in vitro and co-localize in normal and cancer cells Antosiewicz, Anna; Jarmuła, Adam; Przybylska, Dorota Journal of Biomolecular Structure and Dynamics, Vol. 35, Issue 7 https://doi.org/10.1080/07391102.2016.1186560	journal	August 2016
Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates Ribeiro, João Augusto; Chavez-Pacheco, Sair Maximo; de Oliveira, Gabriel Stephani Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 7 https://doi.org/10.1107/s205979831900901x	journal	July 2019
Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates Ribeiro, João Augusto; Chavez-Pacheco, Sair Maximo; de Oliveira, Gabriel Stephani International Union of Crystallography (IUCr) https://doi.org/10.1107/s205979831900901x/ud5007sup1.pdf	text	January 2019
Targeting plant DIHYDROFOLATE REDUCTASE with antifolates and mechanisms for genetic resistance Corral, Maxime G.; Haywood, Joel; Stehl, Luca H. The Plant Journal, Vol. 95, Issue 4 https://doi.org/10.1111/tpj.13983	journal	June 2018
Human dihydrofolate reductase and thymidylate synthase form a complex in vitro and co-localize in normal and cancer cells Antosiewicz, Anna; Jarmuła, Adam; Przybylska, Dorota Taylor & Francis https://doi.org/10.6084/m9.figshare.3543209	text	January 2016

Similar Records

Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate

Journal Article · Sun Nov 21 23:00:00 EST 2010 · Acta Crystallogr. D · OSTI ID:1006151

Induction of gene amplification in Plasmodium falciparum

Thesis/Dissertation · Mon Dec 31 23:00:00 EST 1984 · OSTI ID:7246176

Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Journal Article · Sat Nov 30 23:00:00 EST 2019 · Scientific Reports · OSTI ID:1624518

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
Biochemistry & Molecular Biology
Biophysics
Crystallography

Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

Citation Formats

References (49)

Cited By (7)

Similar Records

Related Subjects