6FFG

Human BRD2 C-terminal bromodomain with (S)-1-(2-cyclopropyl-4-(2-(hydroxymethyl)benzyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone

PDB DOI: https://doi.org/10.2210/pdb6FFG/pdb

Classification: TRANSCRIPTION
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2018-01-07 Released: 2019-01-30
Deposition Author(s): Chung, C.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.59 Å
R-Value Free: 0.205
R-Value Work: 0.170
R-Value Observed: 0.172

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain.

Law, R.P., Atkinson, S.J., Bamborough, P., Chung, C.W., Demont, E.H., Gordon, L.J., Lindon, M., Prinjha, R.K., Watson, A.J.B., Hirst, D.J.

(2018) J Med Chem 61: 4317-4334

PubMed: 29656650 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.7b01666
Primary Citation of Related Structures:
6FFE, 6FFF, 6FFG

PubMed Abstract:
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.

Organizational Affiliation

WestCHEM, Department of Pure and Applied Chemistry , University of Strathclyde, Thomas Graham Building , 295 Cathedral Street , Glasgow , G1 1XL , U.K.

Macromolecule Content

Total Structure Weight: 14.38 kDa
Atom Count: 1,252
Modelled Residue Count: 113
Deposited Residue Count: 115
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Bromodomain-containing protein 2	A	115	Homo sapiens	Mutation(s): 0 Gene Names: BRD2, KIAA9001, RING3
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens) Explore P25440 Go to UniProtKB: P25440
PHAROS: P25440 GTEx: ENSG00000204256
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P25440
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
D7B Query on D7B Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	(S)-1-(2-cyclopropyl-4-(2-(hydroxymethyl)benzyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone C₂₆ H₃₁ N₃ O₂ ARWMKZDWGIOCEU-AREMUKBSSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
MES Query on MES Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A] mmCIF format, chain G [auth A]	G [auth A]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	E [auth A], F [auth A]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A]	B [auth A], C [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A]