Enzymatic and structural characterization of non-peptide ligand-cyclophilin complexes.
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.
Structural Biochemistry Group, Department of Biochemistry, The University of Edinburgh, Michael Swann Building, King's Buildings, Edinburgh EH9 3JR, Scotland.
George
G
Kontopidis
Paul
P
Taylor
Malcolm D
MD
Walkinshaw
D020134:Catalytic Domain; D021983:Cyclophilins / Q000737:chemistry / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity / Q000502:physiology
D008024:Ligands; D010455:Peptides; D010880:Piperidines; D016572:Cyclosporine; D021983:Cyclophilins