PDBsum entry 7ar5

Hydrolase

PDB id: 7ar5

Contents

Protein chain

305 a.a.

Ligands

DMS ×5

Waters ×411

PDB id:

7ar5

Name:

Hydrolase

Title:

Structure of apo sars-cov-2 main protease with small beta angle, space group c2.

Structure:

3c-like proteinase. Chain: a. Synonym: 3cl-pro,3clp,main protease,mpro,non-structural protein 5, nsp5,sars coronavirus main proteinase. Engineered: yes. Other_details: in this structure cysteine 300 is oxidized to hydroxycysteine.

Source:

Severe acute respiratory syndrome coronavirus 2. 2019-ncov, sars-cov-2. Organism_taxid: 2697049. Gene: rep, 1a-1b. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.40Å R-factor: 0.177 R-free: 0.214

Authors:

S.Guenther,P.Reinke,D.Oberthuer,O.Yefanov,L.Gelisio,H.Ginn,J.Lieske, M.Domaracky,W.Brehm,A.Rahmani Mashour,T.A.White,J.Knoska,G.Pena Esperanza,F.Koua,A.Tolstikova,M.Groessler,P.Fischer,V.Hennicke, H.Fleckenstein,F.Trost,M.Galchenkova,Y.Gevorkov,C.Li,S.Awel, L.X.Paulraj,N.Ullah,H.Andaleeb,N.Werner,S.Falke,W.Hinrichs,B.Alves Franca,M.Schwinzer,H.Brognaro,M.Perbandt,H.Tidow,B.Seychell,T.Beck, S.Meier,J.J.Doyle,H.Giseler,D.Melo,I.Dunkel,T.J.Lane,A.Peck, S.Saouane,J.Hakanpaeae,J.Meyer,H.Noei,J.Boger,P.Gribbon,B.Ellinger, M.Kuzikov,M.Wolf,L.Zhang,C.Ehrt,J.Pletzer-Zelgert,J.Wollenhaupt,

Key ref:

S.Günther et al. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science, 372, 642-646. PubMed id: 33811162 DOI: 10.1126/science.abf7945

Date:

23-Oct-20 Release date: 02-Dec-20

Protein chain

P0DTD1  (R1AB_SARS2) -

Enzyme reactions

• Enzyme class: E.C.3.4.22.69 - Sars coronavirus main proteinase.

DOI no: 10.1126/science.abf7945

Science 372:642-646 (2021)

PubMed id: 33811162

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.

S.Günther, P.Y.A.Reinke, Y.Fernández-García, J.Lieske, T.J.Lane, H.M.Ginn, F.H.M.Koua, C.Ehrt, W.Ewert, D.Oberthuer, O.Yefanov, S.Meier, K.Lorenzen, B.Krichel, J.D.Kopicki, L.Gelisio, W.Brehm, I.Dunkel, B.Seychell, H.Gieseler, B.Norton-Baker, B.Escudero-Pérez, M.Domaracky, S.Saouane, A.Tolstikova, T.A.White, A.Hänle, M.Groessler, H.Fleckenstein, F.Trost, M.Galchenkova, Y.Gevorkov, C.Li, S.Awel, A.Peck, M.Barthelmess, F.Schlünzen, P.Lourdu Xavier, N.Werner, H.Andaleeb, N.Ullah, S.Falke, V.Srinivasan, B.A.França, M.Schwinzer, H.Brognaro, C.Rogers, D.Melo, J.J.Zaitseva-Doyle, J.Knoska, G.E.Peña-Murillo, A.R.Mashhour, V.Hennicke, P.Fischer, J.Hakanpää, J.Meyer, P.Gribbon, B.Ellinger, M.Kuzikov, M.Wolf, A.R.Beccari, G.Bourenkov, D.von Stetten, G.Pompidor, I.Bento, S.Panneerselvam, I.Karpics, T.R.Schneider, M.M.Garcia-Alai, S.Niebling, C.Günther, C.Schmidt, R.Schubert, H.Han, J.Boger, D.C.F.Monteiro, L.Zhang, X.Sun, J.Pletzer-Zelgert, J.Wollenhaupt, C.G.Feiler, M.S.Weiss, E.C.Schulz, P.Mehrabi, K.Karničar, A.Usenik, J.Loboda, H.Tidow, A.Chari, R.Hilgenfeld, C.Uetrecht, R.Cox, A.Zaliani, T.Beck, M.Rarey, S.Günther, D.Turk, W.Hinrichs, H.N.Chapman, A.R.Pearson.

ABSTRACT

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^pro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^pro In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.