2h9h › Citations

An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors.

Figure 1
Figure 2
Figure 3
Yin J, Cherney MM, Bergmann EM, Zhang J, Huitema C, Pettersson H, Eltis LD, Vederas JC, James MN
OpenAccess logo J Mol Biol 361 673-86 (2006)
Related entries: 2a4o, 2cxv, 2h6m, 2hal

Cited: 27 times
EuropePMC logo PMID: 16860823

Abstract

We have solved the crystal and molecular structures of hepatitis A viral (HAV) 3C proteinase, a cysteine peptidase having a chymotrypsin-like protein fold, in complex with each of three tetrapeptidyl-based methyl ketone inhibitors to resolutions beyond 1.4 A, the highest resolution to date for a 3C or a 3C-Like (e.g. SARS viral main proteinase) peptidase. The residues of the beta-hairpin motif (residues 138-158), an extension of two beta-strands of the C-terminal beta-barrel of HAV 3C are critical for the interactions between the enzyme and the tetrapeptide portion of these inhibitors that are analogous to the residues at the P4 to P1 positions in the natural substrates of picornaviral 3C proteinases. Unexpectedly, the Sgamma of Cys172 forms two covalent bonds with each inhibitor, yielding an unusual episulfide cation (thiiranium ring) stabilized by a nearby oxyanion. This result suggests a mechanism of inactivation of 3C peptidases by methyl ketone inhibitors that is distinct from that occurring in the structurally related serine proteinases or in the papain-like cysteine peptidases. It also provides insight into the mechanisms underlying both the inactivation of HAV 3C by these inhibitors and on the proteolysis of natural substrates by this viral cysteine peptidase.

Articles - 2h9h mentioned but not cited (3)

  1. Crystal structures of enterovirus 71 3C protease complexed with rupintrivir reveal the roles of catalytically important residues. Wang J, Fan T, Yao X, Wu Z, Guo L, Lei X, Wang J, Wang M, Jin Q, Cui S. J Virol 85 10021-10030 (2011)
  2. An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors. Yin J, Cherney MM, Bergmann EM, Zhang J, Huitema C, Pettersson H, Eltis LD, Vederas JC, James MN. J Mol Biol 361 673-686 (2006)
  3. Structural similarities between SARS-CoV2 3CLpro and other viral proteases suggest potential lead molecules for developing broad spectrum antivirals. Bafna K, Cioffi CL, Krug RM, Montelione GT. Front Chem 10 948553 (2022)


Reviews citing this publication (4)

  1. What coronavirus 3C-like protease tells us: From structure, substrate selectivity, to inhibitor design. Xiong M, Su H, Zhao W, Xie H, Shao Q, Xu Y. Med Res Rev 41 1965-1998 (2021)
  2. Molecular biology and inhibitors of hepatitis A virus. Debing Y, Neyts J, Thibaut HJ. Med Res Rev 34 895-917 (2014)
  3. Direct-acting Antivirals and Host-targeting Agents against the Hepatitis A Virus. Kanda T, Nakamoto S, Wu S, Nakamura M, Jiang X, Haga Y, Sasaki R, Yokosuka O. J Clin Transl Hepatol 3 205-210 (2015)
  4. P1 Glutamine isosteres in the design of inhibitors of 3C/3CL protease of human viruses of the Pisoniviricetes class. Stubbing LA, Hubert JG, Bell-Tyrer J, Hermant YO, Yang SH, McSweeney AM, McKenzie-Goldsmith GM, Ward VK, Furkert DP, Brimble MA. RSC Chem Biol 4 533-547 (2023)

Articles citing this publication (20)

  1. Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses. Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO. J Virol 86 11754-11762 (2012)
  2. Insights into cleavage specificity from the crystal structure of foot-and-mouth disease virus 3C protease complexed with a peptide substrate. Zunszain PA, Knox SR, Sweeney TR, Yang J, Roqué-Rosell N, Belsham GJ, Leatherbarrow RJ, Curry S. J Mol Biol 395 375-389 (2010)
  3. A mechanistic view of enzyme inhibition and peptide hydrolysis in the active site of the SARS-CoV 3C-like peptidase. Yin J, Niu C, Cherney MM, Zhang J, Huitema C, Eltis LD, Vederas JC, James MN. J Mol Biol 371 1060-1074 (2007)
  4. Antiviral zinc oxide nanoparticles mediated by hesperidin and in silico comparison study between antiviral phenolics as anti-SARS-CoV-2. Attia GH, Moemen YS, Youns M, Ibrahim AM, Abdou R, El Raey MA. Colloids Surf B Biointerfaces 203 111724 (2021)
  5. Engineering of protease variants exhibiting altered substrate specificity. Sellamuthu S, Shin BH, Lee ES, Rho SH, Hwang W, Lee YJ, Han HE, Kim JI, Park WJ. Biochem Biophys Res Commun 371 122-126 (2008)
  6. Suppression of La antigen exerts potential antiviral effects against hepatitis A virus. Jiang X, Kanda T, Wu S, Nakamoto S, Saito K, Shirasawa H, Kiyohara T, Ishii K, Wakita T, Okamoto H, Yokosuka O. PLoS One 9 e101993 (2014)
  7. Structural and biochemical analysis of human pathogenic astrovirus serine protease at 2.0 A resolution. Speroni S, Rohayem J, Nenci S, Bonivento D, Robel I, Barthel J, Luzhkov VB, Coutard B, Canard B, Mattevi A. J Mol Biol 387 1137-1152 (2009)
  8. Structures of Enterovirus 71 3C proteinase (strain E2004104-TW-CDC) and its complex with rupintrivir. Wu C, Cai Q, Chen C, Li N, Peng X, Cai Y, Yin K, Chen X, Wang X, Zhang R, Liu L, Chen S, Li J, Lin T. Acta Crystallogr D Biol Crystallogr 69 866-871 (2013)
  9. An engineered viral protease exhibiting substrate specificity for a polyglutamine stretch prevents polyglutamine-induced neuronal cell death. Sellamuthu S, Shin BH, Han HE, Park SM, Oh HJ, Rho SH, Lee YJ, Park WJ. PLoS One 6 e22554 (2011)
  10. Autoproteolytic activation of ThnT results in structural reorganization necessary for substrate binding and catalysis. Buller AR, Labonte JW, Freeman MF, Wright NT, Schildbach JF, Townsend CA. J Mol Biol 422 508-518 (2012)
  11. Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action. Huitema C, Zhang J, Yin J, James MN, Vederas JC, Eltis LD. Bioorg Med Chem 16 5761-5777 (2008)
  12. In silico prediction of SARS protease inhibitors by virtual high throughput screening. Plewczynski D, Hoffmann M, von Grotthuss M, Ginalski K, Rychewski L. Chem Biol Drug Des 69 269-279 (2007)
  13. Toward development of generic inhibitors against the 3C proteases of picornaviruses. Banerjee K, Bhat R, Rao VUB, Nain A, Rallapalli KL, Gangopadhyay S, Singh RP, Banerjee M, Jayaram B. FEBS J 286 765-787 (2019)
  14. A cysteine protease from Spirometra erinaceieuropaei plerocercoid is a critical factor for host tissue invasion and migration. Tsubokawa D, Hatta T, Maeda H, Mikami F, Goso Y, Nakamura T, Alim MA, Tsuji N. Acta Trop 167 99-107 (2017)
  15. NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases. Denesyuk AI, Johnson MS, Salo-Ahen OMH, Uversky VN, Denessiouk K. Int J Biol Macromol 153 399-411 (2020)
  16. Structure of Senecavirus A 3C Protease Revealed the Cleavage Pattern of 3C Protease in Picornaviruses. Meng K, Zhang L, Xue X, Xue Q, Sun M, Meng G. J Virol 96 e0073622 (2022)
  17. Allosteric regulation of Senecavirus A 3Cpro proteolytic activity by an endogenous phospholipid. Zhao HF, Meng L, Geng Z, Gao ZQ, Dong YH, Wang HW, Zhang H. PLoS Pathog 19 e1011411 (2023)
  18. Computer-Aided Prediction of the Interactions of Viral Proteases with Antiviral Drugs: Antiviral Potential of Broad-Spectrum Drugs. Ren P, Li S, Wang S, Zhang X, Bai F. Molecules 29 225 (2023)
  19. From head to toe of the norovirus 3C-like protease. Someya Y. Biomol Concepts 3 41-56 (2012)
  20. Identification of Mulberrofuran as a potent inhibitor of hepatitis A virus 3Cpro and RdRP enzymes through structure-based virtual screening, dynamics simulation, and DFT studies. Sureshan M, Brintha S, Jothi A. Mol Divers (2023)


Related citations provided by authors (1)

  1. Dual modes of modification of hepatitis A virus 3C protease by a serine-derived beta-lactone: selective crystallization and formation of a functional catalytic triad in the active site.. Yin J, Bergmann EM, Cherney MM, Lall MS, Jain RP, Vederas JC, James MN J Mol Biol 354 854-71 (2005)

Quick links