6E4A

Crystal structure of human BRD4(1) in complex with CN750

PDB DOI: https://doi.org/10.2210/pdb6E4A/pdb

Classification: PROTEIN BINDING
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2018-07-17 Released: 2018-09-12
Deposition Author(s): Fontano, E., White, A., Lakshminarasimhan, D., Suto, R.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.26 Å
R-Value Free: 0.189
R-Value Work: 0.162
R-Value Observed: 0.163

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Discovery and lead identification of quinazoline-based BRD4 inhibitors.

Yang, S.M., Urban, D.J., Yoshioka, M., Strovel, J.W., Fletcher, S., Wang, A.Q., Xu, X., Shah, P., Hu, X., Hall, M.D., Jadhav, A., Maloney, D.J.

(2018) Bioorg Med Chem Lett 28: 3483-3488

PubMed: 30268702 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1016/j.bmcl.2018.08.039
Primary Citation of Related Structures:
6E4A

PubMed Abstract:
A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.

Organizational Affiliation

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: [email protected].

Macromolecule Content

Total Structure Weight: 32 kDa
Atom Count: 2,770
Modelled Residue Count: 251
Deposited Residue Count: 258
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 4	A, B	129	Homo sapiens	Mutation(s): 0 Gene Names: BRD4, HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens) Explore O60885 Go to UniProtKB: O60885
PHAROS: O60885 GTEx: ENSG00000141867
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O60885
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HRY Query on HRY Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain E [auth B] MOL2 format, chain C [auth A] MOL2 format, chain E [auth B] mmCIF format, chain C [auth A] mmCIF format, chain E [auth B]	C [auth A], E [auth B]	5-(4-{[(3-chlorophenyl)methyl]amino}-2-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}quinazolin-6-yl)-1-methylpyridin-2(1H)-one C₂₉ H₃₄ Cl N₇ O POKZINYHLOHGEB-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain E [auth B] Interactions & Density Focus chain C [auth A] Focus chain E [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain F [auth B] SDF format, chain G [auth B] MOL2 format, chain D [auth A] MOL2 format, chain F [auth B] MOL2 format, chain G [auth B] mmCIF format, chain D [auth A] mmCIF format, chain F [auth B] mmCIF format, chain G [auth B]	D [auth A], F [auth B], G [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain F [auth B] Focus chain G [auth B] Interactions & Density Focus chain D [auth A] Focus chain F [auth B] Focus chain G [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.26 Å
R-Value Free: 0.189
R-Value Work: 0.162
R-Value Observed: 0.163
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 41.477	α = 90
b = 51.468	β = 90.22
c = 55.297	γ = 90

Software Package:

Software Name	Purpose
SCALEPACK	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction
HKL-2000	data reduction
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-09-12

Deposition Author(s):

Fontano, E.

White, A.

Lakshminarasimhan, D.

Suto, R.K.

Revision History (Full details and data files)

Version 1.0: 2018-09-12
Type: Initial release
Version 1.1: 2018-10-03
Changes: Data collection, Experimental preparation
Version 1.2: 2018-10-10
Changes: Data collection, Database references, Structure summary
Version 1.3: 2018-10-24
Changes: Data collection, Database references, Structure summary
Version 1.4: 2024-03-13
Changes: Data collection, Database references