Structural insights into the catalytic mechanism of cyclophilin A.
Cyclophilins constitute a ubiquitous protein family whose functions include protein folding, transport and signaling. They possess both sequence-specific binding and proline cis-trans isomerase activities, as exemplified by the interaction between cyclophilin A (CypA) and the HIV-1 CA protein. Here, we report crystal structures of CypA in complex with HIV-1 CA protein variants that bind preferentially with the substrate proline residue in either the cis or the trans conformation. Cis- and trans-Pro substrates are accommodated within the enzyme active site by rearrangement of their N-terminal residues and with minimal distortions in the path of the main chain. CypA Arg55 guanidinium group probably facilitates catalysis by anchoring the substrate proline oxygen and stabilizing sp3 hybridization of the proline nitrogen in the transition state.
Howard
Bruce R
BR
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Vajdos
Felix F
FF
Li
Su
S
Sundquist
Wesley I
WI
Hill
Christopher P
CP
D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011392:Proline / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D046911:Macromolecular Substances; D014764:Viral Proteins; D001120:Arginine; D011392:Proline; D021984:Cyclophilin A