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Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease.

Khayat R, Batra R, Qian C, Halmos T, Bailey M, Tong L
Biochemistry 42 885-91 (2003)
Related entries: 1njt, 1nju, 1nkm

Cited: 13 times
EuropePMC logo PMID: 12549906

Abstract

Herpesvirus protease is required for the life cycle of the virus and is an attractive target for the design and development of new anti-herpes agents. The protease belongs to a new class of serine proteases, with a novel backbone fold and a unique Ser-His-His catalytic triad. Here we report the crystal structures of human cytomegalovirus protease in complex with two peptidomimetic inhibitors. The structures reveal a new hydrogen-bonding interaction between the main chain carbonyl of the P(5) residue and the main chain amide of amino acid 137 of the protease, which is important for the binding affinity of the inhibitor. Conformational flexibility was observed in the S(3) pocket of the enzyme, and this is supported by our characterization of several mutants in this pocket. One of the structures is at 2.5 A resolution, allowing us for the first time to locate ordered solvent molecules in the inhibitor complex. The presence of two solvent molecules in the active site may have implications for the design of new inhibitors against this enzyme. Favorable and stereospecific interactions have been established in the S(1)' pocket for one of these inhibitors.

Articles - 1nkk mentioned but not cited (1)

  1. Dimerization-Induced Allosteric Changes of the Oxyanion-Hole Loop Activate the Pseudorabies Virus Assemblin pUL26N, a Herpesvirus Serine Protease. Zühlsdorf M, Werten S, Klupp BG, Palm GJ, Mettenleiter TC, Hinrichs W. PLoS Pathog 11 e1005045 (2015)


Reviews citing this publication (4)

  1. Proteases and protease inhibitors in infectious diseases. Agbowuro AA, Huston WM, Gamble AB, Tyndall JDA. Med Res Rev 38 1295-1331 (2018)
  2. Viral protease inhibitors. Anderson J, Schiffer C, Lee SK, Swanstrom R. Handb Exp Pharmacol 85-110 (2009)
  3. Kaposi's sarcoma-associated herpesvirus: the role of lytic replication in targeted therapy. Andrei G, Snoeck R. Curr Opin Infect Dis 28 611-624 (2015)
  4. Viral proteases as therapeutic targets. Majerová T, Konvalinka J. Mol Aspects Med 88 101159 (2022)

Articles citing this publication (8)

  1. Intrinsic evolutionary constraints on protease structure, enzyme acylation, and the identity of the catalytic triad. Buller AR, Townsend CA. Proc Natl Acad Sci U S A 110 E653-61 (2013)
  2. Communication between the active sites and dimer interface of a herpesvirus protease revealed by a transition-state inhibitor. Marnett AB, Nomura AM, Shimba N, Ortiz de Montellano PR, Craik CS. Proc Natl Acad Sci U S A 101 6870-6875 (2004)
  3. Substrate modulation of enzyme activity in the herpesvirus protease family. Lazic A, Goetz DH, Nomura AM, Marnett AB, Craik CS. J Mol Biol 373 913-923 (2007)
  4. Kinetics, inhibition and oligomerization of Epstein-Barr virus protease. Buisson M, Rivail L, Hernandez JF, Jamin M, Martinez J, Ruigrok RW, Burmeister WP. FEBS Lett 580 6570-6578 (2006)
  5. Chapter 22. Non-HIV antiviral agents. Meanwell NA, Serrano-Wu MH, Snyder LB. Annu Rep Med Chem 38 213-228 (2003)
  6. Dimethylthiazolidine carboxylic acid as a rigid p3 unit in inhibitors of serine proteases: application to two targets. Kawai SH, Aubry N, Duceppe JS, Llinàs-Brunet M, LaPlante SR. Chem Biol Drug Des 74 517-522 (2009)
  7. Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine. Hulce KR, Jaishankar P, Lee GM, Bohn MF, Connelly EJ, Wucherer K, Ongpipattanakul C, Volk RF, Chuo SW, Arkin MR, Renslo AR, Craik CS. Cell Chem Biol 29 785-798.e19 (2022)
  8. Peptide-to-Small Molecule: Discovery of Non-Covalent, Active-Site Inhibitors of β-Herpesvirus Proteases. Yoshida S, Sako Y, Nikaido E, Ueda T, Kozono I, Ichihashi Y, Nakahashi A, Onishi M, Yamatsu Y, Kato T, Nishikawa J, Tachibana Y. ACS Med Chem Lett 14 1558-1566 (2023)


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