PDBsum entry 3v3m

Hydrolase/hydrolase inhibitor

PDB id: 3v3m

Contents

Protein chain

306 a.a.

Ligands

0EN

DMS ×2

Waters ×320

PDB id:

3v3m

Name:

Hydrolase/hydrolase inhibitor

Title:

Severe acute respiratory syndrome coronavirus (sars-cov) 3cl protease in complex with n-[(1r)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl) ethyl]-n-(4-tert-butylphenyl)furan-2-carboxamide inhibitor.

Structure:

3c-like proteinase. Chain: a. Ec: 3.4.19.12, 3.4.22.69, 3.4.22.-. Engineered: yes

Source:

Sars coronavirus. Sars-cov. Organism_taxid: 227859. Gene: 1a. Expressed in: homo sapiens. Expression_system_taxid: 9606

Resolution:

1.96Å R-factor: 0.191 R-free: 0.236

Authors:

J.Jacobs,V.Grum-Tokars,Y.Zhou,M.Turlington,S.A.Saldanha,P.Chase, A.Eggler,E.S.Dawson,Y.M.Baez-Santos,S.Tomar,A.M.Mielech,S.C.Baker, C.W.Lindsley,P.Hodder,A.Mesecar,S.R.Stauffer

Key ref:

J.Jacobs et al. (2013). Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease. J Med Chem, 56, 534-546. PubMed id: 23231439

Date:

13-Dec-11 Release date: 16-Jan-13

Protein chain

P0C6U8  (R1A_CVHSA) -  Replicase polyprotein 1a from Severe acute respiratory syndrome coronavirus

Seq: 4382 a.a.

Struc: 306 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.50 - mRNA guanylyltransferase.
• Reaction: a 5'-end diphospho-ribonucleoside in mRNA + GTP + H⁺ = a 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA + diphosphate
• Enzyme class 2: E.C.3.4.19.12 - ubiquitinyl hydrolase 1.
• Reaction: Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).
• Enzyme class 3: E.C.3.4.22.- - ?????
• Enzyme class 4: E.C.3.4.22.69 - Sars coronavirus main proteinase.

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Med Chem 56:534-546 (2013)

PubMed id: 23231439

Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease.

J.Jacobs, V.Grum-Tokars, Y.Zhou, M.Turlington, S.A.Saldanha, P.Chase, A.Eggler, E.S.Dawson, Y.M.Baez-Santos, S.Tomar, A.M.Mielech, S.C.Baker, C.W.Lindsley, P.Hodder, A.Mesecar, S.R.Stauffer.

ABSTRACT

A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.