PDBsum entry 5i89

Protein binding/inhibitor

PDB id: 5i89

Contents

Protein chain

115 a.a.

Ligands

ACT

69B

Metals

_CA

Waters ×246

PDB id:

5i89

Name:

Protein binding/inhibitor

Title:

Crystal structure of the bromodomain of human crebbp bound to the benzodiazepinone g02857790

Structure:

Creb-binding protein. Chain: a. Fragment: bromodomain (unp residues 1082-1197). Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: crebbp, cbp. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.07Å R-factor: 0.118 R-free: 0.137

Authors:

J.W.Setser,F.Poy,S.F.Bellon

Key ref:

A.M.Taylor et al. (2016). Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637). Acs Med Chem Lett, 7, 531-536. PubMed id: 27190605 DOI: 10.1021/acsmedchemlett.6b00075

Date:

18-Feb-16 Release date: 20-Apr-16

Protein chain

Q92793  (CBP_HUMAN) -  CREB-binding protein from Homo sapiens

Seq: 2442 a.a.

Struc: 115 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.3.1.- - ?????
• Enzyme class 2: E.C.2.3.1.48 - histone acetyltransferase.
• Reaction: L-lysyl-[protein] + acetyl-CoA = N₆-acetyl-L-lysyl-[protein] + CoA + H⁺

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: 10.1021/acsmedchemlett.6b00075

Acs Med Chem Lett 7:531-536 (2016)

PubMed id: 27190605

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).

A.M.Taylor, A.Côté, M.C.Hewitt, R.Pastor, Y.Leblanc, C.G.Nasveschuk, F.A.Romero, T.D.Crawford, N.Cantone, H.Jayaram, J.Setser, J.Murray, M.H.Beresini, G.de Leon Boenig, Z.Chen, A.R.Conery, R.T.Cummings, L.A.Dakin, E.M.Flynn, O.W.Huang, S.Kaufman, P.J.Keller, J.R.Kiefer, T.Lai, Y.Li, J.Liao, W.Liu, H.Lu, E.Pardo, V.Tsui, J.Wang, Y.Wang, Z.Xu, F.Yan, D.Yu, L.Zawadzke, X.Zhu, X.Zhu, R.J.Sims, A.G.Cochran, S.Bellon, J.E.Audia, S.Magnuson, B.K.Albrecht.

ABSTRACT

CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.