PDBsum entry 4mds

Hydrolase/hydrolase inhibitor

PDB id: 4mds

Contents

Protein chain

303 a.a.

Ligands

23H

DMS ×2

Waters ×442

PDB id:

4mds

Name:

Hydrolase/hydrolase inhibitor

Title:

Discovery of n-(benzo[1,2,3]triazol-1-yl)-n-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (sars- cov) 3clpro inhibitors: identification of ml300 and non-covalent nanomolar inhibitors with an induced-fit binding

Structure:

3c-like proteinase. Chain: a. Fragment: unp residues 3241-3542. Synonym: 3cl protease, 3cl-pro, 3clp, nsp5. Engineered: yes

Source:

Sars coronavirus. Sars-cov. Organism_taxid: 227859. Gene: 1a. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.60Å R-factor: 0.172 R-free: 0.212

Authors:

A.D.Mesecar,V.Grum-Tokars

Key ref:

M.Turlington et al. (2013). Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. Bioorg Med Chem Lett, 23, 6172-6177. PubMed id: 24080461 DOI: 10.1016/j.bmcl.2013.08.112

Date:

23-Aug-13 Release date: 02-Oct-13

Protein chain

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

Seq: 4382 a.a.

Struc: 303 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

DOI no: 10.1016/j.bmcl.2013.08.112

Bioorg Med Chem Lett 23:6172-6177 (2013)

PubMed id: 24080461

Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding.

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

ABSTRACT

Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.