Crystal structures of cyclophilin and its partners.
Cyclophilin (CyP) is a cytosolic receptor of immunosuppressive drug cyclosporin A (CsA). The binary complex of CyP-CsA inhibits the activity of Ca2+/calmodulin dependent serine/threonine calcineurin (CN). The inhibition of CN in turn disables the transcription activity of nuclear factor of activated T cell, thus suppressing the T cell activation and cardiac hypertrophy. CyP is also an enzyme catalyzing peptidyl-prolyl cis-trans isomerization and serves as a molecular chaperone in various biological processes. For example, CyPA is involved in the assembly/deassembly of HIV-1 virion and is required for the full infectious activity of HIV-1. However, the in vivo function of CyP remains a mystery. This review will describe the three-dimensional structures of CyPs and its partners and discuss the structural clues to understanding the CyP functions in biological processes. The structures of CyP in complex with proline-containing peptides provided insight into the mechanism of peptidyl-prolyl cis-trans isomerization. The structures of CyPA in complex with HIV-1 capsid protein and its peptides revealed details of interactions of CyP with HIV-1 capsid protein, thus providing a guideline for design of anti-HIV drugs. The rearrangement of two tetratricopeptide repeats of the, large, cyclophilin CyP40 into a long helix under the crystallization conditions might be biologically relevant to the CyP40 function in the hsp90 molecular chaperone system. The structures of the binary CyPA-CsA and ternary CN-CyPA-CsA complexes showed how CsA binds to its receptors and therefore provide a template for design of new immunosuppressive drugs.
Ke
Hengming
H
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA. hke@med.unc.edu
Huai
Qing
Q
D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D021983:Cyclophilins / Q000737:chemistry*; D016572:Cyclosporine / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D014158:Transcription, Genetic
D036022:Capsid Proteins; D007166:Immunosuppressive Agents; D010455:Peptides; D016572:Cyclosporine; D021983:Cyclophilins