3qyr › Citations

Increasing the structural coverage of tuberculosis drug targets.

Baugh L, Phan I, Begley DW, Clifton MC, Armour B, Dranow DM, Taylor BM, Muruthi MM, Abendroth J, Fairman JW, Fox D, Dieterich SH, Staker BL, Gardberg AS, Choi R, Hewitt SN, Napuli AJ, Myers J, Barrett LK, Zhang Y, Ferrell M, Mundt E, Thompkins K, Tran N, Lyons-Abbott S, Abramov A, Sekar A, Serbzhinskiy D, Lorimer D, Buchko GW, Stacy R, Stewart LJ, Edwards TE, Van Voorhis WC, Myler PJ
Tuberculosis (Edinb) 95 142-8 (2015)

Cited: 50 times
EuropePMC logo PMID: 25613812

Abstract

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.

Reviews citing this publication (6)

  1. Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells. Abu-Remaileh M, Joy-Dodson E, Schueler-Furman O, Aqeilan RI. J Biol Chem 290 30728-30735 (2015)
  2. Insights into multifaceted activities of CysK for therapeutic interventions. Joshi P, Gupta A, Gupta V. 3 Biotech 9 44 (2019)
  3. Impact of Genomics on Clarifying the Evolutionary Relationships amongst Mycobacteria: Identification of Molecular Signatures Specific for the Tuberculosis-Complex of Bacteria with Potential Applications for Novel Diagnostics and Therapeutics. Gupta RS. High Throughput 7 E31 (2018)
  4. Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS). Pozzi C, Lopresti L, Tassone G, Mangani S. Molecules 24 E1638 (2019)
  5. Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae. Vedithi SC, Malhotra S, Acebrón-García-de-Eulate M, Matusevicius M, Torres PHM, Blundell TL. Front Mol Biosci 8 663301 (2021)
  6. Flavin-dependent thymidylate synthase: N5 of flavin as a Methylene carrier. Karunaratne K, Luedtke N, Quinn DM, Kohen A. Arch Biochem Biophys 632 11-19 (2017)

Articles citing this publication (44)

  1. Structures of the calcium-activated, non-selective cation channel TRPM4. Guo J, She J, Zeng W, Chen Q, Bai XC, Jiang Y. Nature 552 205-209 (2017)
  2. Structural basis for cytokinin production by LOG from Corynebacterium glutamicum. Seo H, Kim S, Sagong HY, Son HF, Jin KS, Kim IK, Kim KJ. Sci Rep 6 31390 (2016)
  3. Decoding the similarities and differences among mycobacterial species. Malhotra S, Vedithi SC, Blundell TL. PLoS Negl Trop Dis 11 e0005883 (2017)
  4. Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches. Whitehouse AJ, Thomas SE, Brown KP, Fanourakis A, Chan DS, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG. J Med Chem 62 7210-7232 (2019)
  5. Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW. McKary MG, Abendroth J, Edwards TE, Johnson RJ. Biochemistry 55 7099-7111 (2016)
  6. Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification. Thomas SE, Whitehouse AJ, Brown K, Burbaud S, Belardinelli JM, Sangen J, Lahiri R, Libardo MDJ, Gupta P, Malhotra S, Boshoff HIM, Jackson M, Abell C, Coyne AG, Blundell TL, Floto RA, Mendes V. Nucleic Acids Res 48 8099-8112 (2020)
  7. Structural characterization and functional analysis of cystathionine β-synthase: an enzyme involved in the reverse transsulfuration pathway of Bacillus anthracis. Devi S, Abdul Rehman SA, Tarique KF, Gourinath S. FEBS J 284 3862-3880 (2017)
  8. On the evolution of the quality of macromolecular models in the PDB. Brzezinski D, Dauter Z, Minor W, Jaskolski M. FEBS J 287 2685-2698 (2020)
  9. Letter The structure of a Trypanosoma cruzi glucose-6-phosphate dehydrogenase reveals differences from the mammalian enzyme. Mercaldi GF, Dawson A, Hunter WN, Cordeiro AT. FEBS Lett 590 2776-2786 (2016)
  10. Biochemical Characterization and Structural Modeling of Fused Glucose-6-Phosphate Dehydrogenase-Phosphogluconolactonase from Giardia lamblia. Morales-Luna L, Serrano-Posada H, González-Valdez A, Ortega-Cuellar D, Vanoye-Carlo A, Hernández-Ochoa B, Sierra-Palacios E, Rufino-González Y, Castillo-Rodríguez RA, Pérez de la Cruz V, Moreno-Vargas L, Prada-Gracia D, Marcial-Quino J, Gómez-Manzo S. Int J Mol Sci 19 E2518 (2018)
  11. Investigation of the anti-TB potential of selected propolis constituents using a molecular docking approach. Ali MT, Blicharska N, Shilpi JA, Seidel V. Sci Rep 8 12238 (2018)
  12. Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase. Ajalla Aleixo MA, Rangel VL, Rustiguel JK, de Pádua RAP, Nonato MC. FEBS J 286 1925-1940 (2019)
  13. Determinants of Cofactor Specificity for the Glucose-6-Phosphate Dehydrogenase from Escherichia coli: Simulation, Kinetics and Evolutionary Studies. Fuentealba M, Muñoz R, Maturana P, Krapp A, Cabrera R. PLoS One 11 e0152403 (2016)
  14. Crystal structures of cyanobacterial light-dependent protochlorophyllide oxidoreductase. Dong CS, Zhang WL, Wang Q, Li YS, Wang X, Zhang M, Liu L. Proc Natl Acad Sci U S A 117 8455-8461 (2020)
  15. Predictive Binding Affinity of Plant-Derived Natural Products Towards the Protein Kinase G Enzyme of Mycobacterium tuberculosis (MtPknG). Qasaymeh RM, Rotondo D, Oosthuizen CB, Lall N, Seidel V. Plants (Basel) 8 E477 (2019)
  16. A LONELY GUY protein of Bordetella pertussis with unique features is related to oxidative stress. Moramarco F, Pezzicoli A, Salvini L, Leuzzi R, Pansegrau W, Balducci E. Sci Rep 9 17016 (2019)
  17. Engineering Archeal Surrogate Systems for the Development of Protein-Protein Interaction Inhibitors against Human RAD51. Moschetti T, Sharpe T, Fischer G, Marsh ME, Ng HK, Morgan M, Scott DE, Blundell TL, R Venkitaraman A, Skidmore J, Abell C, Hyvönen M. J Mol Biol 428 4589-4607 (2016)
  18. A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466. Xie Y, Feng Y, Di Capua A, Mak T, Buchko GW, Myler PJ, Liu M, Quinn RJ. Mar Drugs 18 E149 (2020)
  19. Crystal structure of a hemerythrin-like protein from Mycobacterium kansasii and homology model of the orthologous Rv2633c protein of M. tuberculosis. Ma Z, Abendroth J, Buchko GW, Rohde KH, Davidson VL. Biochem J 477 567-581 (2020)
  20. Integrated Target-Based and Phenotypic Screening Approaches for the Identification of Anti-Tubercular Agents That Bind to the Mycobacterial Adenylating Enzyme MbtA. Ferguson L, Wells G, Bhakta S, Johnson J, Guzman J, Parish T, Prentice RA, Brucoli F. ChemMedChem 14 1735-1741 (2019)
  21. Structural and functional insight into serine hydroxymethyltransferase from Helicobacter pylori. Sodolescu A, Dian C, Terradot L, Bouzhir-Sima L, Lestini R, Myllykallio H, Skouloubris S, Liebl U. PLoS One 13 e0208850 (2018)
  22. Structural insight into molecular mechanism of cytokinin activating protein from Pseudomonas aeruginosa PAO1. Seo H, Kim KJ. Environ Microbiol 20 3214-3223 (2018)
  23. fDETECT webserver: fast predictor of propensity for protein production, purification, and crystallization. Meng F, Wang C, Kurgan L. BMC Bioinformatics 18 580 (2018)
  24. Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors. Hernández-Ochoa B, Navarrete-Vázquez G, Aguayo-Ortiz R, Ortiz-Ramírez P, Morales-Luna L, Martínez-Rosas V, González-Valdez A, Gómez-Chávez F, Enríquez-Flores S, Wong-Baeza C, Baeza-Ramírez I, Pérez de la Cruz V, Gómez-Manzo S. Molecules 26 4955 (2021)
  25. Investigation of pyrophosphate versus ATP substrate selection in the Entamoeba histolytica acetate kinase. Dang T, Ingram-Smith C. Sci Rep 7 5912 (2017)
  26. Structural insight for substrate tolerance to 2-deoxyribose-5-phosphate aldolase from the pathogen Streptococcus suis. Cao TP, Kim JS, Woo MH, Choi JM, Jun Y, Lee KH, Lee SH. J Microbiol 54 311-321 (2016)
  27. The crystal structures of Thermus thermophilus CMP kinase complexed with a phosphoryl group acceptor and donor. Mega R, Nakagawa N, Kuramitsu S, Masui R. PLoS One 15 e0233689 (2020)
  28. Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives. Venugopala KN, Al-Shar'i NA, Dahabiyeh LA, Hourani W, Deb PK, Pillay M, Abu-Irmaileh B, Bustanji Y, Chandrashekharappa S, Tratrat C, Attimarad M, Nair AB, Sreeharsha N, Shinu P, Haroun M, Kandeel M, Balgoname AA, Venugopala R, Morsy MA. Antibiotics (Basel) 11 831 (2022)
  29. Crystal Structures of Apo and Liganded 4-Oxalocrotonate Decarboxylase Uncover a Structural Basis for the Metal-Assisted Decarboxylation of a Vinylogous β-Keto Acid. Guimarães SL, Coitinho JB, Costa DM, Araújo SS, Whitman CP, Nagem RA. Biochemistry 55 2632-2645 (2016)
  30. Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics. Yagmurov E, Tsibulskaya D, Livenskyi A, Serebryakova M, Wolf YI, Borukhov S, Severinov K, Dubiley S. mBio 11 e00497-20 (2020)
  31. Structural Genomics Support for Infectious Disease Drug Design. Stacy R, Anderson WF, Myler PJ. ACS Infect Dis 1 127-129 (2015)
  32. Trichomonas vaginalis metalloproteinase TvMP50 is a monomeric Aminopeptidase P-like enzyme. Arreola R, Villalpando JL, Puente-Rivera J, Morales-Montor J, Rudiño-Piñera E, Alvarez-Sánchez ME. Mol Biotechnol 60 563-575 (2018)
  33. Structural diversity in the Mycobacteria DUF3349 superfamily. Buchko GW, Abendroth J, Robinson JI, Phan IQ, Myler PJ, Edwards TE. Protein Sci 29 670-685 (2020)
  34. A complete nicotinate degradation pathway in the microbial eukaryote Aspergillus nidulans. Bokor E, Ámon J, Varga M, Szekeres A, Hegedűs Z, Jakusch T, Szakonyi Z, Flipphi M, Vágvölgyi C, Gácser A, Scazzocchio C, Hamari Z. Commun Biol 5 723 (2022)
  35. Ab initio structure solution of a proteolytic fragment using ARCIMBOLDO. Abendroth J, Sankaran B, Myler PJ, Lorimer DD, Edwards TE. Acta Crystallogr F Struct Biol Commun 74 530-535 (2018)
  36. Crystal structure of a short-chain dehydrogenase/reductase from Burkholderia phymatum in complex with NAD. Alenazi J, Mayclin S, Subramanian S, Myler PJ, Asojo OA. Acta Crystallogr F Struct Biol Commun 78 52-58 (2022)
  37. Decrypting the programming of β-methylation in virginiamycin M biosynthesis. Collin S, Cox RJ, Paris C, Jacob C, Chagot B, Weissman KJ, Gruez A. Nat Commun 14 1327 (2023)
  38. Effects of secondary infections on the multidrug-resistant Tuberculosis: A cohort study. Tabriz N, Nurtazina ZB, Kozhamuratov MT, Skak K, Mutaikhan Z. Med J Islam Repub Iran 35 105 (2021)
  39. From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma. Lykins J, Moschitto MJ, Zhou Y, Filippova EV, Le HV, Tomita T, Fox BA, Bzik DJ, Su C, Rajagopala SV, Flores K, Spano F, Woods S, Roberts CW, Hua C, El Bissati K, Wheeler KM, Dovgin S, Muench SP, McPhillie M, Fishwick CWG, Anderson WF, Lee PJ, Hickman M, Weiss LM, Dubey JP, Lorenzi HA, Silverman RB, McLeod RL. iScience 27 108477 (2024)
  40. Mechanism of Naphthoquinone Selectivity of Thymidylate Synthase ThyX. Myllykallio H, Becker HF, Aleksandrov A. Biophys J 119 2508-2516 (2020)
  41. Mycobacterium Cytidylate Kinase Appears to Be an Undruggable Target. Craig JK, Risler JK, Loesch KA, Dong W, Baker D, Barrett LK, Subramanian S, Samudrala R, Van Voorhis WC. J Biomol Screen 21 695-700 (2016)
  42. Patulin Stimulates Progenitor Leydig Cell Proliferation but Delays Its Differentiation in Male Rats during Prepuberty. Li H, Su M, Lin H, Li J, Wang S, Ye L, Li X, Ge R. Toxins (Basel) 15 581 (2023)
  43. Synthesis and Structure-Activity Relationship Studies of Pyrido [1,2-e]Purine-2,4(1H,3H)-Dione Derivatives Targeting Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis. Biteau NG, Roy V, Nicolas C, Becker HF, Lambry JC, Myllykallio H, Agrofoglio LA. Molecules 27 6216 (2022)
  44. dUMP/F-dUMP Binding to Thymidylate Synthase: Human Versus Mycobacterium tuberculosis. Gaurav K, Adhikary T, Satpati P. ACS Omega 5 17182-17192 (2020)


Quick links