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Structural insights into the catalytic mechanism of cyclophilin A

Nature Structural & Molecular Biology volume 10, pages 475–481 (2003)Cite this article

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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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Figure 1: Overall structure of CypA–CAN complexes.
Figure 2: Comparison of CAN loop conformations.
Figure 3: Proposed reaction pathway.
Figure 4: Superposition of CypA complexes with the cis conformations of CAN and Suc-Ala-Ala-Pro-Phe-NA (ref. 23).

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  • 12 May 2003

    footnote in HTML, errata last page of AOP PDF

Notes

  1. 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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Author notes

  1. Bruce R Howard, Felix F Vajdos and Su Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, 84132, Utah, USA

    Bruce R Howard, Felix F Vajdos, Su Li, Wesley I Sundquist & Christopher P Hill

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Correspondence to Wesley I Sundquist or Christopher P Hill.

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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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