[Frontiers in Bioscience 9, 2285-2296, September 1, 2004]
CRYSTAL STRUCTURES OF CYCLOPHILIN AND ITS PARTNERS
Hengming Ke and Qing Huai
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA
TABLE OF CONTENTS
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.