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Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease

Nature Structural Biology volume 5, pages 819–826 (1998)Cite this article

Abstract

Human cytomegalovirus (HCMV) protease belongs to a new class of serine proteases, with a unique polypeptide backbone fold. The crystal structure of the protease in complex with a peptidomimetic inhibitor (based on the natural substrates and covering the P4 to P1' positions) has been determined at 2.7 Å resolution. The inhibitor is bound in an extended conformation, forming an anti-parallel ß-sheet with the protease. The P3 and P1 side chains are less accessible to solvent, whereas the P4 and P2 side chains are more exposed. The inhibitor binding mode shows significant similarity to those observed for peptidomimetic inhibitors or substrates of other classes of serine proteases (chymotrypsin and subtilisin). HCMV protease therefore represents example of convergent evolution. In addition, large conformational differences relative to the structure of the free enzyme are observed, which may be important for inhibitor binding.

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Figure 1: Chemical structure of the peptidomimetic inhibitor BILC 821 of HCMV protease.
Figure 2: Schematic drawing30 of the structure of HCMV protease in complex with the inhibitor BILC 821.
Figure 3: Superposition of the Cα trace of HCMV protease in complex with BILC 821 (cyan) and the free enzyme (yellow)3.
Figure 4: Schematic drawing showing the interactions between the main chain atoms of the BILC 821 inhibitor and HCMV protease.
Figure 5: Comparison of the molecular surface31 near the active site of HCMV protease a, in complex with the inhibitor BILC 821, and b, in the free enzyme structure3.
Figure 6: Conserved mode of binding of peptide inhibitors (substrates) to HCMV protease (in cyan for carbon atoms), chymotrypsin (yellow), and subtilisin (green).

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Acknowledgements

We thank W. Davidson for characterization of the protein samples by mass spectrometry, C. Chabot for the synthesis of BILC 821, and D. Cameron for helpful comments.

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  1. Liang Tong

    Present address: Department of Biological Sciences, Columbia University, New York, New York, 10027, USA

Authors and Affiliations

  1. Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road / P.O. Box 368, Ridgefield, 06877, Connecticut, USA

    Liang Tong & Chungeng Qian

  2. Bio-Méga Research Division,, Boehringer Ingelheim (Canada) Ltd., 2100 rue Cunard, Laval, Québec, H7S 2G5, Canada

    Marie-Josée Massariol, Robert Déziel, Christiane Yoakim & Lisette Lagacé

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Correspondence to Liang Tong.

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Tong, L., Qian, C., Massariol, MJ. et al. Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease. Nat Struct Mol Biol 5, 819–826 (1998). https://doi.org/10.1038/1860

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