4OVH

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

Summary for 4OVH

• Entry DOI: 10.2210/pdb4ovh/pdb
• Related: 4OVF 4OVG 4PNU 4PNV 4PNW
• Descriptor: DNA polymerase III subunit beta, DI(HYDROXYETHYL)ETHER, (2R)-6-bromo-9-{2-[(carboxymethyl)amino]-2-oxoethyl}-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid, ... (7 entities in total)
• Functional Keywords: poliii beta, sliding clamp, dnan, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 82470.60

Authors

Yin, Z.,Oakley, A.J. (deposition date: 2014-02-21, release date: 2014-03-05, Last modification date: 2023-09-20)

Primary citation

Yin, Z.,Whittell, L.R.,Wang, Y.,Jergic, S.,Ma, C.,Lewis, P.J.,Dixon, N.E.,Beck, J.L.,Kelso, M.J.,Oakley, A.J.
Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs.
J.Med.Chem., 58:4693-4702, 2015

PubMed 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.

PubMed: 25970224
DOI: 10.1021/acs.jmedchem.5b00232

Experimental method

X-RAY DIFFRACTION (2.25 Å)