PDBsum entry 5cgp

Transcription/inhibitor

PDB id: 5cgp

Contents

Protein chain

115 a.a.

Ligands

53W

Waters ×59

PDB id:

5cgp

Name:

Transcription/inhibitor

Title:

Selective pharmacological inhibition of the creb binding protein bromodomain regulates inflammatory cytokines in macrophages and rgs4 in neurons

Structure:

Creb-binding protein. Chain: a. Fragment: unp residues 1081-1197. Engineered: yes

Source:

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

Resolution:

1.96Å R-factor: 0.213 R-free: 0.249

Authors:

E.L.Chekler,L.H.Jones

Key ref:

E.L.Chekler et al. (2015). Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities. Chem Biol, 22, 1588-1596. PubMed id: 26670081 DOI: 10.1016/j.chembiol.2015.10.013

Date:

09-Jul-15 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: 10.1016/j.chembiol.2015.10.013

Chem Biol 22:1588-1596 (2015)

PubMed id: 26670081

Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.

E.L.Chekler, J.A.Pellegrino, T.A.Lanz, R.A.Denny, A.C.Flick, J.Coe, J.Langille, A.Basak, S.Liu, I.A.Stock, P.Sahasrabudhe, P.D.Bonin, K.Lee, M.T.Pletcher, L.H.Jones.

ABSTRACT

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.