PDBsum entry 5i1q

Protein binding/inhibitor

PDB id: 5i1q

Contents

Protein chain

135 a.a.

Ligands

67C

Waters ×175

PDB id:

5i1q

Name:

Protein binding/inhibitor

Title:

Second bromodomain of taf1 bound to a pyrrolopyridone compound

Structure:

Transcription initiation factor tfiid subunit 1. Chain: a. Fragment: second bromodomain (unp residues 1497-1638). Synonym: cell cycle gene 1 protein, tbp-associated factor 250 kda, p250, transcription initiation factor tfiid 250 kda subunit, tafii250. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: taf1, ba2r, ccg1, ccgs, taf2a. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.50Å R-factor: 0.187 R-free: 0.214

Authors:

Y.Tang,F.Poy,S.F.Bellon

Key ref:

T.D.Crawford et al. (2016). Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains. J Med Chem, 59, 5391-5402. PubMed id: 27219867 DOI: 10.1021/acs.jmedchem.6b00264

Date:

09-Jan-16 Release date: 08-Jun-16

Protein chain

P21675  (TAF1_HUMAN) -  Transcription initiation factor TFIID subunit 1 from Homo sapiens

Seq: 1872 a.a.

Struc: 135 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.3.1.48 - histone acetyltransferase.
• Reaction: L-lysyl-[protein] + acetyl-CoA = N₆-acetyl-L-lysyl-[protein] + CoA + H⁺
• Enzyme class 2: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + 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

reference

DOI no: 10.1021/acs.jmedchem.6b00264

J Med Chem 59:5391-5402 (2016)

PubMed id: 27219867

Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains.

T.D.Crawford, V.Tsui, E.M.Flynn, S.Wang, A.M.Taylor, A.Côté, J.E.Audia, M.H.Beresini, D.J.Burdick, R.Cummings, L.A.Dakin, M.Duplessis, A.C.Good, M.C.Hewitt, H.R.Huang, H.Jayaram, J.R.Kiefer, Y.Jiang, J.Murray, C.G.Nasveschuk, E.Pardo, F.Poy, F.A.Romero, Y.Tang, J.Wang, Z.Xu, L.E.Zawadzke, X.Zhu, B.K.Albrecht, S.R.Magnuson, S.Bellon, A.G.Cochran.

ABSTRACT

The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.