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The tem-per-ature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro).

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Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA
OpenAccess logo IUCrJ 9 682-694 (2022)
Related entries: 7mhf, 7mhg, 7mhh, 7mhi, 7mhj, 7mhk, 7mhl

Cited: 15 times
EuropePMC logo PMID: 36071812

Abstract

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic tem-per-ature or room tem-per-ature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple tem-per-atures from cryogenic to physiological, and another at high humidity. We inter-rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for Mpro, including a mobile zinc ion inter-leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra-molecular network bridging the active site and dimer inter-face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.

Articles - 7mhm mentioned but not cited (3)

  1. The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro). Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA. IUCrJ 9 682-694 (2022)
  2. Validation of X-ray Crystal Structure Ensemble Representations of SARS-CoV-2 Main Protease by Solution NMR Residual Dipolar Couplings. Shen Y, Robertson AJ, Bax A. J Mol Biol 168067 (2023)
  3. research-article The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro). Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA. bioRxiv 2021.05.03.437411 (2021)


Articles citing this publication (12)

  1. Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L. Costanzi E, Kuzikov M, Esposito F, Albani S, Demitri N, Giabbai B, Camasta M, Tramontano E, Rossetti G, Zaliani A, Storici P. Int J Mol Sci 22 11779 (2021)
  2. The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature. Correy GJ, Kneller DW, Phillips G, Pant S, Russi S, Cohen AE, Meigs G, Holton JM, Gahbauer S, Thompson MC, Ashworth A, Coates L, Kovalevsky A, Meilleur F, Fraser JS. Sci Adv 8 eabo5083 (2022)
  3. Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B. Skaist Mehlman T, Biel JT, Azeem SM, Nelson ER, Hossain S, Dunnett L, Paterson NG, Douangamath A, Talon R, Axford D, Orins H, von Delft F, Keedy DA. Elife 12 e84632 (2023)
  4. Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3-d]pyrimidines as potential active site inhibitors and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro. Mousavi H, Zeynizadeh B, Rimaz M. Bioorg Chem 135 106390 (2023)
  5. Understanding Cysteine Chemistry Using Conventional and Serial X-Ray Protein Crystallography. Smith N, Wilson MA. Crystals (Basel) 12 1671 (2022)
  6. Introduction to the virtual thematic issue on room-temperature biological crystallography. Steiner RA. IUCrJ 10 248-250 (2023)
  7. Introduction to the virtual thematic issue on room-temperature biological crystallography. Steiner RA. Acta Crystallogr F Struct Biol Commun 79 79-81 (2023)
  8. Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design. Funk LM, Poschmann G, Rabe von Pappenheim F, Chari A, Stegmann KM, Dickmanns A, Wensien M, Eulig N, Paknia E, Heyne G, Penka E, Pearson AR, Berndt C, Fritz T, Bazzi S, Uranga J, Mata RA, Dobbelstein M, Hilgenfeld R, Curth U, Tittmann K. Nat Commun 15 411 (2024)
  9. Perspective: Structure determination of protein-ligand complexes at room temperature using X-ray diffraction approaches. Hough MA, Prischi F, Worrall JAR. Front Mol Biosci 10 1113762 (2023)
  10. Pushed to extremes: distinct effects of high temperature versus pressure on the structure of STEP. Guerrero L, Ebrahim A, Riley BT, Kim M, Huang Q, Finke AD, Keedy DA. Commun Biol 7 59 (2024)
  11. Synergism between x-ray crystallography and NMR residual dipolar couplings in characterizing protein dynamics. Shen Y, Bax A. Struct Dyn 10 040901 (2023)
  12. Understanding the role of water on temperature-dependent structural modifications of SARS CoV-2 main protease binding sites. Venugopal PP, Singh O, Chakraborty D. J Mol Liq 363 119867 (2022)


Related citations provided by authors (3)

  1. The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro).. Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA bioRxiv (2021)
  2. The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro). Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA IUCrJ 9 - (2022)
  3. The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro).. Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA bioRxiv (2021)

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