Abstract
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.
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Change history
12 May 2003
footnote in HTML, errata last page of AOP PDF
Notes
Note: In the version of this article initially published online, the sequence for the model tetrapeptide substrate contains a mistake. This incorrect sequence is listed in two places, on page 4 line 21 and line 25 of the right hand column. The correct sequence should be Suc-Ala-Phe-Pro-Phe-NA. This mistake has been corrected for the HTML and print versions of the article.
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Acknowledgements
We thank D.R. Davis, S.L. Alam, T.E. Cheatham III and members of the Hill and Sundquist labs for comments on this manuscript; H. Ke for providing processed structure factor amplitudes for the CypA–tetrapeptide structure; H.L. Schubert for help with refinement; and G.N. Murshudov for modifying REFMAC5 to allow the refinement of peptide structures containing prolines with partial cis and partial trans conformations. Operations of the Advanced Light Source, National Synchrotron Light Source and Stanford Synchrotron Radiation Laboratory are supported by the U.S. Department of Energy, Office of Basic Energy Sciences, and by the National Institutes of Health. This work was supported by NIH grants to W.I.S. and C.P.H.
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Howard, B., Vajdos, F., Li, S. et al. Structural insights into the catalytic mechanism of cyclophilin A. Nat Struct Mol Biol 10, 475–481 (2003). https://doi.org/10.1038/nsb927
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DOI: https://doi.org/10.1038/nsb927
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