The active site of an enzyme can host both enantiomers of a racemic ligand simultaneously

Angewandte Chemie - International Edition

Volumn 48, Issue 48, 2009, Pages 9084-9087

  Mentel, Matthias ^a,c,d   Blankenfeldt, Wulf ^a,b   Breinbauer, Rolf ^b,c  

^a MAX PLANCK INSTITUTE OF MOLECULAR PHYSIOLOGY   (Germany)

^b GRAZ UNIVERSITY OF TECHNOLOGY   (Austria)

^c UNIVERSITY OF LEIPZIG   (Germany)

^d EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Germany)

Author keywords

Biosynthesis; Chirality; Drug design; Medicinal chemistry; Protein structures

Indexed keywords

ACTIVE SITE; BINDING MODES; CHIRAL DRUGS; DRUG DESIGN; HOMODIMERIC ENZYME; MEDICINAL CHEMISTRY; PROTEIN CRYSTALLOGRAPHY; PROTEIN STRUCTURES; RACEMIC LIGANDS;

BINDING ENERGY; BIOCHEMISTRY; BIOSYNTHESIS; CHIRALITY; CRYSTALLOGRAPHY; ENZYMES; LIGANDS; STEREOCHEMISTRY;

ENANTIOMERS;

LIGAND; PHENAZINE DERIVATIVE;

ARTICLE; BURKHOLDERIA CEPACIA; CHEMICAL STRUCTURE; ENZYME ACTIVE SITE; ENZYMOLOGY; METABOLISM; PROTEIN MULTIMERIZATION; PROTEIN QUATERNARY STRUCTURE; STEREOISOMERISM; THERMODYNAMICS;

BURKHOLDERIA CEPACIA; CATALYTIC DOMAIN; LIGANDS; MODELS, MOLECULAR; PHENAZINES; PROTEIN MULTIMERIZATION; PROTEIN STRUCTURE, QUATERNARY; STEREOISOMERISM; THERMODYNAMICS;

EID: 70449562080     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/anie.200902997     Document Type: Article

References (31)

1. a) L. Pasteur, C. R. Hebd. Seances Acad. Sci. 1858, 46, 615-618;
2. b) J. Gal, Chirality 2008, 20, 5-19.
3. a) E. J. Ariens, Med. Res. Rev. 1986, 6, 451-466;
4. b) M. Simonyi, Med. Res. Rev. 1984, 4, 359-413.
5. I. Agranat, H. Caner, J. Caldwell, Nat Rev. Drug Discovery 2002, 1, 753-768.
6. http ://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucml22883.htm
7. a) P. Beroza, M. J. Suto, Drug Discovery Today Drug Discov. Today 2000, 5, 364-372;
8. b) W H. Brooks, K. G. Daniel, S.-S. Sung, W. C. Guida, J. Chem. Inf. Model. 2008, 48, 639-645.
9. J. Fokkens, G. Klebe, Angew. Chem. 2006, 118, 1000-1004;
10. Angew. Chem. Int. Ed. 2006, 45, 985-989.
11. X-ray structures of protein complexes in which a binding pocket can be occupied by each enantiomer individually, have been reported: a) A. Mezzetti, J. D. Schräg, C. S. Cheong, R. J. Kazlauskas, Chem. Biol. 2005, 12, 427-437;
12. b) M. Bocola, M. T. Stubbs, C. Sotriffer, B. Hauer, T. Friedrich, K. Dittrich, G. Klebe, Protein Eng. 2003, 16, 319-322;
13. (c) I. Petitpas, A.A. Bhattacharya, S. Twine, M. East, S. Curry, J Biol. Chem. 2001, 276, 22804-22809;
14. (d) B. P. Klaholz, A. Mitschler, M. Belema, C. Zusi, D. Moras, Proc. Natl. Acad. Sci. USA 2000, 97, 6322-6327;
15. e) C. R. D. Lancaster, H. Michel, J. Mol. Biol. 1999, 256, 883898;
16. f) V S. Stoll, B. T. Eger, R. C. Hynes, V Martichonok, J. B. Jones, E. F. Pai, Biochemistry 1998, 37, 451-462;
17. g) D. A. Lang, M. L. M. Mannesse, G. H. de Haas, H. M. Verheij, B. W Dijkstra, Eur. J. Biochem. 1998, 254, 333-340;
18. h) M. T. Stubbs, R. Huber, W Bode, FEBS Lett. 1995, 375, 103-107;
19. (i) M. Cygler, P. Grochulski, R. J. Kazlauskas, J. D. Schrag, F. Bouthillier, B. Rubin, A. N Serreqi, A. K. Gupta, J. Am. Chem. Soc. 1994, 116, 3180-3186;
20. j) R. Raag, H. Li, B.C. Jones, T.L. Poulos, Biochemistry 1993, 32, 4571-4578;
21. k) M. Karpusas, D. Holland, S. J. Remington, Biochemistry 1991, 30, 6024-6031.
22. E. G. Ahuja, P. Janning, M. Mentel, A. Graebsch, R. Breinbauer, W Hiller, B. Costisella, L. S. Thomashow, D. V Mavrodi, W Blankenfeldt, J. Am. Chem. Soc. 2008, 130, 17053-17061.
23. a) S. G. Aller, J. Yu, A. Ward, Y. Weng, S. Chittaboina, R. Zhuo, P. M. Harrell, Y. T. Trinh, Q. Zhang, I. L. Urbatsch, G. Chang, Science 2009, 323, 1718-1722;
24. b) M. Ekroos, T. Sjögren, Proc. Natl. Acad. Sci. USA 2006, 103, 13682-13687.
25. Reviews: a) "Methods and Principles of Medicinal Chemistry": Fragment-Based Approaches in Drug Discovery, Vol.34 (Eds. : W Jahnke, D. A. Erlanson, R. Mannhold, H. Kubinyi, G. Folkers), Wiley-VCH, Weinheim, 2006;
26. b) D. C Rees, M. Congreve, C. W. Murray, R. Carr, Nat. Rev. Drug Discovery 2004, 3, 660-672.
27. S. V Ley, A. W Thomas, Angew. Chem. 2003, 115, 5558-5607;
28. Angew. Chem. Int. Ed. 2003, 42, 5400-5449;
29. Corrigendum: S. V. Ley, A. W Thomas, Angew. Chem. 2004, 116, 1061;
30. Angew. Chem. Int. Ed. 2004, 43, 1043.
31. Coordinates and structure factors have been deposited in the Protein Data Bank (PDB) with access codes 3JUM, 3JUN, 3JUO, 3JUP and 3JUQ.