5NU5

Crystal structure of the human bromodomain of EP300 bound to the inhibitor XDM-CBP

PDB DOI: https://doi.org/10.2210/pdb5NU5/pdb

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

Deposited: 2017-04-28 Released: 2017-08-16
Deposition Author(s): Huegle, M., Wohlwend, D.
Funding Organization(s): German Research Foundation

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.60 Å
R-Value Free: 0.185
R-Value Work: 0.162
R-Value Observed: 0.163

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles.

Hugle, M., Lucas, X., Ostrovskyi, D., Regenass, P., Gerhardt, S., Einsle, O., Hau, M., Jung, M., Breit, B., Gunther, S., Wohlwend, D.

(2017) Angew Chem Int Ed Engl 56: 12476-12480

PubMed: 28766825 Search on PubMed
DOI: https://doi.org/10.1002/anie.201705516
Primary Citation of Related Structures:
5LPJ, 5LPK, 5LPL, 5LPM, 5NRW, 5NU3, 5NU5

PubMed Abstract:
Bromodomain and extra-terminal domain (BET) inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. XDM-CBP is a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. Along with X-ray crystal-structure analysis and thermodynamic profiling, XDM-CBP was used in screenings of several cancer cell lines in vitro to study its inhibitory potential on cancer cell proliferation. XDM-CBP is demonstrated to be a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia.

Organizational Affiliation

Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104, Freiburg, Germany.

Macromolecule Content

Total Structure Weight: 28.7 kDa
Atom Count: 2,445
Modelled Residue Count: 232
Deposited Residue Count: 232
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Histone acetyltransferase p300	A, B	116	Homo sapiens	Mutation(s): 0 Gene Names: EP300, P300 EC: 2.3.1.48 (PDB Primary Data), 2.3.1 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q09472 (Homo sapiens) Explore Q09472 Go to UniProtKB: Q09472
PHAROS: Q09472 GTEx: ENSG00000100393
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q09472
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
99E Query on 99E Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain H [auth B] mmCIF format, chain C [auth A] mmCIF format, chain H [auth B]	C [auth A], H [auth B]	~{N}-[[2,8-bis(oxidanyl)naphthalen-1-yl]methyl]-4-ethanoyl-3-ethyl-5-methyl-1~{H}-pyrrole-2-carboxamide C₂₁ H₂₂ N₂ O₄ KCGVENSOXCWCNF-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain H [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain I [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain I [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain I [auth B]	D [auth A], E [auth A], F [auth A], G [auth A], I [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
99E	BindingDB: 5NU5	Kd: min: 230, max: 470 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.60 Å
R-Value Free: 0.185
R-Value Work: 0.162
R-Value Observed: 0.163
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 37.92	α = 90
b = 82.433	β = 110.77
c = 42.608	γ = 90

Software Package:

Software Name	Purpose
XDS	data reduction
Aimless	data scaling
PHASER	phasing
REFMAC	refinement
PDB_EXTRACT	data extraction

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2017-08-16

Deposition Author(s):

Huegle, M.

Wohlwend, D.

Funding Organization	Location	Grant Number
German Research Foundation	Germany	WO 2012/1-1

Revision History (Full details and data files)

Version 1.0: 2017-08-16
Type: Initial release
Version 1.1: 2017-10-11
Changes: Database references
Version 1.2: 2024-01-17
Changes: Data collection, Database references, Refinement description