5A83 | pdb_00005a83

Crystal structure of human ATAD2 bromodomain in complex with 4-((3R, 4R)-4-3-methyl-5-(5-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinolin-8- yl-aminopiperidin-3-yloxymethyl)-1-thiane-1,1-dione

PDB DOI: https://doi.org/10.2210/pdb5A83/pdb

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

Deposited: 2015-07-11 Released: 2015-08-12
Deposition Author(s): Chung, C., Bamborough, P., Demont, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.09 Å
R-Value Free:
0.211 (Depositor), 0.220 (DCC)
R-Value Work:
0.170 (Depositor), 0.180 (DCC)
R-Value Observed:
0.172 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structure-Based Optimization of Naphthyridones Into Potent Atad2 Bromodomain Inhibitors.

Bamborough, P., Chung, C., Furze, R.C., Grandi, P., Michon, A., Sheppard, R.J., Barnett, H., Diallo, H., Dixon, D.P., Douault, C., Jones, E.J., Karamshi, B., Mitchell, D.J., Prinjha, R.K., Rau, C., Watson, R.J., Werner, T., Demont, E.H.

(2015) J Med Chem 58: 6151

PubMed: 26230603 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.5b00773
Primary Citation of Related Structures:
5A81, 5A82, 5A83, 5A85

PubMed Abstract:
ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.

Organizational Affiliation

∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Macromolecule Content

Total Structure Weight: 16.34 kDa
Atom Count: 1,374
Modelled Residue Count: 130
Deposited Residue Count: 130
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
ATPASE FAMILY AAA DOMAIN-CONTAINING PROTEIN 2	A	130	Homo sapiens	Mutation(s): 0 EC: 3.6.1.3 (PDB Primary Data), 3.6.1 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q6PL18 (Homo sapiens) Explore Q6PL18 Go to UniProtKB: Q6PL18
PHAROS: Q6PL18 GTEx: ENSG00000156802
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q6PL18
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
YD3 Query on YD3 Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	8-[[(3R,4R)-3-[[1,1-bis(oxidanylidene)thian-4-yl]methoxy]piperidin-4-yl]amino]-3-methyl-5-(5-methylpyridin-3-yl)-1H-quinolin-2-one C₂₇ H₃₄ N₄ O₄ S KXXIBIBXJMYWNL-ILBGXUMGSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A]	F [auth A], G [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain F [auth A] Focus chain G [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	B [auth A], C [auth A], D [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
YD3	BindingDB: 5A83	Kd: min: 7.9, max: 90 (nM) from 4 assay(s)
YD3	BindingDB: 5A83	IC50: min: 40, max: 158 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.09 Å
R-Value Free: 0.211 (Depositor), 0.220 (DCC)
R-Value Work: 0.170 (Depositor), 0.180 (DCC)
R-Value Observed: 0.172 (Depositor)

Space Group: P 6₅ 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 79.172	α = 90
b = 79.172	β = 90
c = 137.617	γ = 120

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
SCALA	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-08-12

Deposition Author(s):

Chung, C.

Bamborough, P.

Demont, E.

Revision History (Full details and data files)

Version 1.0: 2015-08-12
Type: Initial release
Version 1.1: 2015-08-26
Changes: Database references
Version 1.2: 2019-05-15
Changes: Data collection, Derived calculations, Experimental preparation, Other
Version 1.3: 2024-05-08
Changes: Data collection, Database references, Derived calculations, Other