Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase

Journal of Medicinal Chemistry

Volumn 58, Issue 8, 2015, Pages 3572-3581

  Salo Ahen, Outi M H ^a,g   Tochowicz, Anna ^b   Pozzi, Cecilia ^c   Cardinale, Daniela ^d,h   Ferrari, Stefania ^d   Boum, Yap ^e   Mangani, Stefano ^c   Stroud, Robert M ^b   Saxena, Puneet ^d   Myllykallio, Hannu ^e   Costi, Maria Paola ^d   Ponterini, Glauco ^d   Wade, Rebecca C ^a,f  

^a HEIDELBERG INSTITUTE FOR THEORETICAL STUDIES   (Germany)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF SIENA   (Italy)

^d UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^e LABORATOIRE D OPTIQUE ET BIOSCIENCES   (France)

^f UNIVERSITY OF HEIDELBERG   (Germany)

^g ÅBO AKADEMI UNIVERSITY   (Finland)

^h UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; ANTINEOPLASTIC AGENT; ARGININE; HOMODIMER; HUMAN THYMIDYLATE SYNTHASE; THYMIDYLATE SYNTHASE; UNCLASSIFIED DRUG; ENZYME INHIBITOR;

ARTICLE; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; ENZYME ACTIVITY; ENZYME INACTIVATION; ENZYME KINETICS; FLUORESCENCE RESONANCE ENERGY TRANSFER; POINT MUTATION; PROTEIN PROTEIN INTERACTION; PROTEIN SECONDARY STRUCTURE; WILD TYPE; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; ENZYME ACTIVATION; ENZYMOLOGY; GENETICS; HUMAN; METABOLISM; MOLECULAR DOCKING; NEOPLASMS; PROTEIN CONFORMATION; PROTEIN MULTIMERIZATION;

ANTINEOPLASTIC AGENTS; ENZYME ACTIVATION; ENZYME INHIBITORS; HUMANS; MOLECULAR DOCKING SIMULATION; NEOPLASMS; POINT MUTATION; PROTEIN CONFORMATION; PROTEIN MULTIMERIZATION; THYMIDYLATE SYNTHASE;

EID: 84928474035     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00137     Document Type: Article

References (52)

1. Carreras, C. W.; Santi, D. V. The catalytic mechanism and structure of thymidylate synthase Annu. Rev. Biochem. 1995, 64, 721-762
2. Cardinale, D.; Guaitoli, G.; Tondi, D.; Luciani, R.; Henrich, S.; Salo-Ahen, O. M.; Ferrari, S.; Marverti, G.; Guerrieri, D.; Ligabue, A.; Frassineti, C.; Pozzi, C.; Mangani, S.; Fessas, D.; Guerrini, R.; Ponterini, G.; Wade, R. C.; Costi, M. P. Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase Proc. Natl. Acad. Sci. U.S.A. 2011, 108, E542-E549
3. Garg, D.; Henrich, S.; Salo-Ahen, O. M. H.; Myllykallio, H.; Costi, M. P.; Wade, R. C. Novel approaches for targeting thymidylate synthase to overcome the resistnace and toxicity of anticancer drugs J. Med. Chem. 2010, 53, 6539-6549
4. Phan, J.; Koli, S.; Minor, W.; Dunlap, R. B.; Berger, S. H.; Lebioda, L. Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug Biochemistry 2001, 40, 1897-1902
5. Schiffer, C. A.; Clifton, I. J.; Davisson, V. J.; Santi, D. V.; Stroud, R. M. Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site Biochemistry 1995, 34, 16279-16287
6. Perry, K. M.; Pookanjanatavip, M.; Zhao, J.; Santi, D. V.; Stroud, R. M. reversible dissociation and unfolding of the dimeric protein thymidylate synthase Protein Sci. 1992, 1, 796-800
7. Maley, F.; Pedersen-Lane, J.; Changchien, L. Complete restoration of activity to inactive mutants of Escherichia coli thymidylate synthase: evidence that E. coli thymidylate synthase is a half-the-sites activity enzyme Biochemistry 1995, 34, 1469-1474
8. Saxl, R. L.; Changchien, L. M.; Hardy, L. W.; Maley, F. Parameters affecting the restoration of activity to inactive mutants of thymidylate synthase via subunit exchange: further evidence that thymidylate synthase is a half-of-the-sites activity enzyme Biochemistry 2001, 40, 5275-5282
9. Saxl, R. L.; Maley, G. F.; Hauer, C. R.; Maccoll, R.; Changchien, L.; Maley, F. Significance of mutations on the structural perturbation of thymidylate synthase: implications for their involvement in subunit exchange Protein Sci. 2007, 16, 1439-1448
10. Genovese, F.; Ferrari, S.; Guaitoli, G.; Caselli, M.; Costi, M. P.; Ponterini, G. Dimer-monomer equilibrium of human thymidylate synthase monitored by fluorescence resonance energy transfer Protein Sci. 2010, 19, 1023-1030
11. Chu, E.; Koeller, D. M.; Casey, J. L.; Drake, J. C.; Chabner, B. A.; Elwood, P. C.; Zinn, S.; Allegra, C. J. Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8977-8981
12. Liu, J.; Schmitz, J. C.; Lin, X.; Tai, N.; Yan, W.; Farrell, M.; Bailly, M.; Chen, T.; Chu, E. Thymidylate synthase as a translational regulator of cellular gene expression Biochim. Biophys. Acta 2002, 1587, 174-182
13. Berger, S. H.; Berger, F. G.; Lebioda, L. Effects of ligand binding and conformational switching on intracellular stability of human thymidylate synthase Biochim. Biophys. Acta 2004, 1696, 15-22
14. Lin, X.; Liu, J.; Maley, F.; Chu, E. Role of cysteine amino acid residues on the RNA binding activity of human thymidylate synthase Nucleic Acids Res. 2003, 31, 4882-4887
15. Voeller, D. M.; Zajac-Kaye, M.; Fisher, R. J.; Allegra, C. J. The identification of thymidylate synthase peptide domains located in the interface region that bind thymidylate synthase mRNA Biochem. Biophys. Res. Commun. 2002, 297, 24-31
16. Bogan, A. A.; Thorn, K. S. Anatomy of hot spots in protein interfaces J. Mol. Biol. 1998, 280, 1-9
17. Clackson, T.; Wells, J. A. A hot spot of binding energy in a hormone-receptor interface Science 1995, 267, 383-386
18. Keskin, O.; Ma, B.; Nussinov, R. Hot regions in protein-protein interactions: the organization and contribution of structurally conserved hot spot residues J. Mol. Biol. 2005, 345, 1281-1294
19. Gao, Y.; Wang, R.; Lai, L. Structure-based method for analyzing protein-protein interfaces J. Mol. Model. 2004, 10, 44-54
20. Halperin, I.; Wolfson, H.; Nussinov, R. Protein-protein interactions; coupling of structurally conserved residues and of hot spots across interfaces. Implications for docking Structure 2004, 12, 1027-1038
21. Kortemme, T.; Baker, D. A simple physical model for binding energy hot spots in protein-protein complexes Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14116-14121
22. Pons, J.; Rajpal, A.; Kirsch, J. F. Energetic analysis of an antigen/antibody interface: alanine scanning mutagenesis and double mutant cycles on the HyHEL-10/lysozyme interaction Protein Sci. 1999, 8, 958-968
23. Zerbe, B. S.; Hall, D. R.; Vajda, S.; Whitty, A.; Kozakov, D. Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces J. Chem. Inf. Model. 2012, 52, 2236-2244
24. Brandsdal, B. O.; Smalas, A. O. Evaluation of protein-protein association energies by free energy perturbation calculations Protein Eng. 2000, 13, 239-245
25. Darnell, S. J.; Page, D.; Mitchell, J. C. An automated decision-tree approach to predicting protein interaction hot spots Proteins 2007, 68, 813-823
26. del Sol, A.; O'Meara, P. Small-world network approach to identify key residues in protein-protein interaction Proteins 2005, 58, 672-682
27. Guerois, R.; Nielsen, J. E.; Serrano, L. Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations J. Mol. Biol. 2002, 320, 369-387
28. Tochowicz, A.; Matteo Santucci, M.; Saxena, P.; Giambattista, G.; Trande, M.; Finer-Moore, J.; Stroud, R. M.; Costi, M. P. Alanine mutants of the interface residues of human thymidylate synthase decode key features of the binding mode of allosteric anticancer peptides J. Med. Chem. 2015, 58 (2) 1012-1018
29. Schymkowitz, J.; Borg, J.; Stricher, F.; Nys, R.; Rousseau, F.; Serrano, L. The FoldX web server: an online force field Nucleic Acids Res. 2005, 33, W382-W388
30. Kortemme, T.; Kim, D. E.; Baker, D. Computational alanine scanning of protein-protein interfaces Sci. STKE 2004, pl2
31. Parthiban, V.; Gromiha, M. M.; Schomburg, D. CUPSAT: prediction of protein stability upon point mutations Nucleic Acids Res. 2006, 34, W239-W242
32. Phan, J.; Steadman, D. J.; Koli, S.; Ding, W. C.; Minor, W.; Dunlap, R. B.; Berger, S. H.; Lebioda, L. Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors J. Biol. Chem. 2001, 276, 14170-14177
33. Lovelace, L. L.; Minor, W.; Lebioda, L. Structure of human thymidylate synthase under low-salt conditions Acta Crystallogr., Sect. D: Biol. Crystallogr. 2005, 61, 622-627
34. Almog, R.; Waddling, C. A.; Maley, F.; Maley, G. F.; Van Roey, P. Crystal structure of a deletion mutant of human thymidylate synthase delta (7-29) and its ternary complex with Tomudex and dUMP Protein Sci. 2001, 10, 988-996
35. Sayre, P. H.; Finer-Moore, J. S.; Fritz, T. A.; Biermann, D.; Gates, S. B.; MacKellar, W. C.; Patel, V. F.; Stroud, R. M. Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases J. Mol. Biol. 2001, 313, 813-829
36. Lovelace, L. L.; Johnson, S. R.; Gibson, L. M.; Bell, B. J.; Berger, S. H.; Lebioda, L. Variants of human thymidylate synthase with loop 181-197 stabilized in the inactive conformation Protein Sci. 2009, 18, 1628-1636
37. Landis, D. M.; Gerlach, J. L.; Adman, E. T.; Loeb, L. A. Tolerance of 5-fluorodeoxyuridine resistant human thymidylate synthases to alterations in active site residues Nucleic Acids Res. 1999, 27, 3702-3711
38. Salo-Ahen, O. M.; Wade, R. C. The active-inactive transition of human thymidylate synthase: targeted molecular dynamics simulations Proteins 2011, 79, 2886-2899
39. Carosati, E.; Tochowicz, A.; Marverti, G.; Guaitoli, G.; Benedetti, P.; Ferrari, S.; Stroud, R. M.; Finer-Moore, J.; Luciani, R.; Farina, D.; Cruciani, G.; Costi, M. P. Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase J. Med. Chem. 2012, 55, 10272-10276
40. Tong, Y.; Liu-Chen, X.; Ercikan-Abali, E. A.; Capiaux, G. M.; Zhao, S. C.; Banerjee, D.; Bertino, J. R. Isolation and characterization of thymitaq (AG337) and 5-fluoro-2-deoxyuridylate-resistant mutants of human thymidylate synthase from ethyl methanesulfonate-exposed human sarcoma HT1080 cells J. Biol. Chem. 1998, 273, 11611-11618
41. Landis, D. M.; Heindel, C. C.; Loeb, L. A. Creation and characterization of 5-fluorodeoxyuridine-resistant Arg50 loop mutants of human thymidylate synthase Cancer Res. 2001, 61, 666-672
42. Michaels, M. L.; Kim, C. W.; Matthews, D. A.; Miller, J. H. Escherichia coli thymidylate synthase: amino acid substitutions by suppression of amber nonsense mutations Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 3957-3961
43. West, D. K.; Porter, D. C.; Saxl, R. L.; Maley, F. A Trojan horse approach for silencing thymidylate synthase Biochemistry 2004, 43, 9177-9184
44. Strop, P.; Changchien, L.; Maley, F.; Montfort, W. R. Crystal structures of a marginally active thymidylate synthase mutant, Arg 126 - >Glu Protein Sci. 1997, 6, 2504-2511
45. Michaels, M. L.; Kim, C. W.; Matthews, D. A.; Miller, J. H. Escherichia coli thymidylate synthase: amino acid substitutions by suppression of amber nonsense mutations Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 3957-3961
46. Prasanna, V.; Gopal, B.; Murthy, M. R.; Santi, D. V.; Balaram, P. Effect of amino acid substitutions at the subunit interface on the stability and aggregation properties of a dimeric protein: role of Arg 178 and Arg 218 at the Dimer interface of thymidylate synthase Proteins 1999, 34, 356-368
47. Kawase, S.; Cho, S. W.; Rozelle, J.; Stroud, R. M.; Finer-Moore, J.; Santi, D. V. Replacement set mutagenesis of the four phosphate-binding arginine residues of thymidylate synthase Protein Eng. 2000, 13, 557-563
48. Landis, D. M.; Loeb, L. A. Random sequence mutagenesis and resistance to 5-fluorouridine in human thymidylate synthases J. Biol. Chem. 1998, 273, 25809-25817
49. Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank Nucleic Acids Res. 2000, 28, 235-242
50. Glaser, F.; Pupko, T.; Paz, I.; Bell, R. E.; Bechor-Shental, D.; Martz, E.; Ben-Tal, N. ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information Bioinformatics 2003, 19, 163-164
51. Landau, M.; Mayrose, I.; Rosenberg, Y.; Glaser, F.; Martz, E.; Pupko, T.; Ben-Tal, N. ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures Nucleic Acids Res. 2005, 33, W299-W302
52. Benvenuti, M.; Mangani, S. Crystallization of soluble proteins in vapor diffusion for X-ray crystallography Nat. Protoc. 2007, 2, 1633-1651