PDBsum entry 4ovh

Transferase/transferase inhibitor

PDB id: 4ovh

Contents

Protein chains

362 a.a.

Ligands

PEG ×5

2VE

PG4

Metals

_CA

_CL

Waters ×321

PDB id:

4ovh

Name:

Transferase/transferase inhibitor

Title:

E. Coli sliding clamp in complex with (r)-6-bromo-9-(2- (carboxymethylamino)-2-oxoethyl)-2,3,4,9-tetrahydro-1h-carbazole-2- carboxylic acid

Structure:

DNA polymerase iii subunit beta. Chain: a, b. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 1403831. Strain: k-12 substr. Mc4100. Gene: bn896_3391, dnan. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.25Å R-factor: 0.192 R-free: 0.250

Authors:

Z.Yin,A.J.Oakley

Key ref:

Z.Yin et al. (2015). Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs. J Med Chem, 58, 4693-4702. PubMed id: 25970224 DOI: 10.1021/acs.jmedchem.5b00232

Date:

21-Feb-14 Release date: 05-Mar-14

Protein chains

U6NCW5  (U6NCW5_ECOLI) -

Enzyme reactions

• Enzyme class: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate

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

Added reference

DOI no: 10.1021/acs.jmedchem.5b00232

J Med Chem 58:4693-4702 (2015)

PubMed id: 25970224

Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs.

Z.Yin, L.R.Whittell, Y.Wang, S.Jergic, C.Ma, P.J.Lewis, N.E.Dixon, J.L.Beck, M.J.Kelso, A.J.Oakley.

ABSTRACT

The bacterial DNA replication machinery presents new targets for the development of antibiotics acting via novel mechanisms. One such target is the protein-protein interaction between the DNA sliding clamp and the conserved peptide linear motifs in DNA polymerases. We previously established that binding of linear motifs to the Escherichia coli sliding clamp occurs via a sequential mechanism that involves two subsites (I and II). Here, we report the development of small-molecule inhibitors that mimic this mechanism. The compounds contain tetrahydrocarbazole moieties as "anchors" to occupy subsite I. Functional groups appended at the tetrahydrocarbazole nitrogen bind to a channel gated by the side chain of M362 and lie at the edge of subsite II. One derivative induced the formation of a new binding pocket, termed subsite III, by rearrangement of a loop adjacent to subsite I. Discovery of the extended binding area will guide further inhibitor development.