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1mik

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THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A

Structural highlights

1mik is a 2 chain structure with sequence from Homo sapiens and Tolypocladium inflatum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.76Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PPIA_HUMAN PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).

The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A.,Mikol V, Papageorgiou C, Borer X J Med Chem. 1995 Aug 18;38(17):3361-7. PMID:7650689^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mikol V, Papageorgiou C, Borer X. The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A. J Med Chem. 1995 Aug 18;38(17):3361-7. PMID:7650689