Redesigning small molecule-protein interfaces

Current Opinion in Structural Biology

Volumn 8, Issue 4, 1998, Pages 451-458

  Clackson, Tim ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CYCLOPHILIN A; CYCLOSPORIN; HORMONE RECEPTOR; IMMUNOPHILIN; MUTANT PROTEIN; PROTEINASE; RAPAMYCIN;

ARTICLE; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG PROTEIN BINDING; PRIORITY JOURNAL; PROTEIN BINDING;

EID: 0032142906     PISSN: 0959440X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-440X(98)80122-X     Document Type: Article

References (33)

1. Babine RE, Bender SL. Molecular recognition of protein-ligand complexes; applications to drug design. of special interest Chem Rev. 97:1997;1359-1472 An extremely long but useful and well-organized discussion of the process of structure-based drug design and the factors that contribute to the binding affinity and specificity of protein ligands. Although biased towards protease inhibitors, it includes case histories of many other systems, including FKBP ligands. Intelligible to the structurally minded nonchemist.
2. Wilson KP, McCaffrey PG, Hsiao K, Pazhanisamy S, Galullo V, Bemis GW, Fitzgibbon MJ, Caron PR, Murcko MA, Su MS. The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase. Chem Biol. 4:1997;423-431.
3. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 384:1996;644-648.
4. Hung DT, Jamison TF, Schreiber SL. Understanding and controlling the cell cycle with natural products. Chem Biol. 3:1996;623-639.
5. Spencer DM, Wandless TJ, Schreiber SL, Crabtree GR. Controlling signal transduction with synthetic ligands. Science. 262:1993;1019-1024.
6. Spencer DM. Creating conditional mutations in mammals. Trends Genet. 12:1996;191-197.
7. Mitchison TJ. Towards a pharmacological genetics. Chem Biol. 1:1994;3-6.
8. Crews CM. Deciphering isozyme function: exploring cell biology with chemistry in the post-genomic era. Chem Biol. 3:1996;961-965.
9. Black ME, Newcomb TG, Wilson HM, Loob LA. Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc Natl Acad Sci USA. 93:1996;3525-3529.
10. Kast P, Hilvert D. 3D structural information as a guide to protein engineering using genetic selection. Curr Opin Struct Biol. 7:1997;470-479.
11. Zhao H, Arnold FH. Combinatorial protein design: strategies for screening protein libraries. Curr Opin Struct Biol. 7:1997;480-485.
12. 6-(cyclopentyl) - ATP and V323A/I338A v-Src solution.
13. m now equivalent to that of the wild-type enzyme with ATP. They also demonstrate that the same combination works in the context of the related Src family kinase Fyn.
14. 50 = 0.43 μM) was used to reverse the dominant transforming phenotype of I338G v-Src in transfected fibroblasts.
15. 8-(benzyl)-ATP were designed and tested in order to support the hypothesis. The introduction also contains a useful discussion of the other methods that have been used to generate 'orthogonal' ligand systems.
16. Carter P, Wells JA. Engineering enzyme specificity by "substrate-assisted catalysis" Science. 237:1987;394-399.
17. Smith GK, Banks S, Blumenkopf TA, Cory M, Humphreys J, Laethem RM, Miller J, Moxham CP, Mullin R, Ray PH, et al. Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate. of outstanding interest J Biol Chem. 272:1997;15804-15816 A very detailed description of the redesign of human carboxypeptidase A1 so that it will accept prodrugs comprising methotrexate coupled to an unnatural bumped amino acid, for eventual use in antibody-directed tumor chemotherapy. A single mutation produced a more than 10,000-fold shift in the catalytic activity of the enzyme for the best bumped substrate.
18. Katzenellenbogen JA, Katzenellenbogen BS. Nuclear hormone receptors: ligand-activated regulators of transcription and diverse cell responses. Chem Biol. 3:1996;529-536.
19. Peet DJ, Doyle DF, Corey Dr, Mangelsdorf DJ. Engineering novel specificities for ligand-activated transcription in the nuclear hormone receptor RXR. of special interest Chem Biol. 5:1998;13-21 The retinoic acid receptor (RXR) was mutated at Phe313 and/or Leu436 and tested for its ability to bind and activate transcription in response to the natural ligand 9-cis retinoic acid (9cRA) or three synthetic ligands. Some mutations conferred selectivity for the synthetic compounds whereas others only retained responsivity to 9cRA. Structural interpretation is complicated by the lack of a 9cRA-RXR co-complex structure and the involvement of conformational changes.
20. Schreiber SL. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 251:1991;283-287.
21. Ciardy J. The chemistry of signal transduction. Proc Natl Acad Sci USA. 92:1995;56-61.
22. Crabtree GR, Schreiber SL. Three-part inventions: Intracellular signaling and induced proximity. Trends Biochem Sci. 21:1996;418-422.
23. Belshaw PJ, Schoepfer JG, Liu KQ, Morrison KL, Schreiber SL. Rational design of orthogonal receptor-ligand combinations. Angew Chem Int Ed. 34:1995;2129-2132.
24. Pierce AC, Jorgensen WL. Computational binding studies of orthogonal cyclosporin-cyclophilin pairs. of special interest Angew Chem Int Ed. 36:1997;1466-1469 Monte-Carlo simulations were run for some of the ligand pairs described in [23]. The findings were largely consistent with experimental binding data and suggest that water molecules may occupy the unfilled void in F113A cyclophilin A.
25. Belshaw PJ, Schreiber SL. Cell-specific calcineurin inhibition by a modified cyclosporin. of outstanding interest J Am Chem Soc. 119:1997;1805-1806 The first generation bump - hole pairing of V11 cyclosporin A (CsA) and F113A/S99T cyclophilin A (Cyp) [23] was improved by enlarging the bump and then further truncating F113 to glycine, followed by 'back filling' to improve complementarily. The cyclopentyl-bumped CsA allows calcineurin inhibition to be restricted to cells expressing the mutant Cyp.
26. Rivera VM, Clarkson T, Natesan S, Pollock R, Amara JF, Keenan T, Magari SR, Phillips T, Courage NL, Cerasoli F Jr, et al. A humanized system for pharmacologic control of gene expression. Nat Med. 2:1996;1028-1032.
27. 50 for transcription from ~ 500 nM to 10 nM.
28. d = 0.1 nM) and 1 000-fold specificity for the designed FKBP mutant F36V. The crystal structure of the remodelled complex shows that the ethyl 'bump' only partially fills the engineered hole, leaving an enclosed void of ~60 Å at the interface.
29. Ridgway JB, Presta LG, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 9:1996;617-621.
30. Zhu Z, Presta LG, Zapata G, Carter P. Remodeling domain interfaces to enhance heterodimer formation. Protein Sci. 6:1997;781-788.
31. Atweil S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol. 270:1997;26-35.
32. 2 interface.
33. Eriksson AE, Baase WA, Zhang XJ, Heinz DW, Blaber M, Baldwin EP, Matthews BW. Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. Science. 255:1992;178-183.