PDBsum entry 1w8v

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Isomerase PDB id
Protein chain
165 a.a. *
Waters ×192
* Residue conservation analysis

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Key reference
Title Enzymatic and structural characterization of non-Peptide ligand-Cyclophilin complexes.
Authors G.Kontopidis, P.Taylor, M.D.Walkinshaw.
Ref. Acta Crystallogr D Biol Crystallogr, 2004, 60, 479-485. [DOI no: 10.1107/S0907444904000174]
PubMed id 14993672
Piperidine ligands are described that provide the first examples of non-peptidic ligand structures for the cyclophilin family of proteins. Crystal structures of two ligand complexes are compared with the unliganded protein and show ligand-induced changes in side-chain conformation and water binding. A peptidylprolyl cis-trans-isomerase assay showed the dissociation constants of the two ligands to be 320 and 25 mM. This study also provides the first published data for both enzymatic activity and three-dimensional structure for any protein-ligand complex that binds with a high-millimolar dissociation constant. The structures may be of relevance in the field of drug design, as they suggest starting points for the design of larger tighter-binding analogues.
Figure 3.
Figure 3 (a) Overlay of native hCypA (cyan) with hCypA-ACMPIP (atom-type colours). Close contacts between the ACMPIP ligand with surrounding atoms are shown. ACMPIP makes one hydrogen bond to Asn102 N (2.8 ). The most hydrophobic part of the ACMPIP molecule (the methylpiperidine ring) fits into the hydrophobic pocket. van der Waals contacts are made from the ligand to the side chains of six amino acids (Arg55, Phe 60, Met61, Gln63, Phe113 and His126). (b) Overlay of native hCypA (cyan) with the hCypA-ETPIPG in both binding modes (ALT2, green; ALT1, purple). The main difference between the native protein structure and the structure with ETPIPG in the binding site is the movement of the side chain of Met61. The overall backbone conformations of the three structures are very similar. An r.m.s. fit of all protein atoms except residues 1-4, 67-76 and 162-165 between native and the ACMPIP complex is 0.286 and that between the ACMPIP and ETPIPG complexes is 0.367 .
Figure 5.
Figure 5 Diagrammatic representation of the major ligand-protein interactions. Hydrogen bonds are shown as dotted lines. The hydrophobic pocket is primarily bounded by the side chains of Phe113 and Phe60, which are shown as green ovals.
The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2004, 60, 479-485) copyright 2004.
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