6GIP

Crystal structure of the ACVR1 (ALK2) kinase in complex with a Quinazolinone based ALK2 inhibitor with a 2, 5-dimethyl core.

PDB DOI: https://doi.org/10.2210/pdb6GIP/pdb

Classification: SIGNALING PROTEIN
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): Yes

Deposited: 2018-05-14 Released: 2018-05-23
Deposition Author(s): Williams, E., Hudson, L., Bezerra, G.A., Sorrell, F., Mathea, S., Chen, Z., Mahajan, P., Kupinska, K., Hoelder, S., Burgess-Brown, N., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Bullock, A.N.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.17 Å
R-Value Free: 0.239
R-Value Work: 0.195

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.

Hudson, L., Mui, J., Vazquez, S., Carvalho, D.M., Williams, E., Jones, C., Bullock, A.N., Hoelder, S.

(2018) J Med Chem 61: 7261-7272

PubMed: 30085668 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.8b00782
Primary Citation of Related Structures:
6GI6, 6GIN, 6GIP

PubMed Abstract:
Structure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.

Organizational Affiliation

Institute of Cancer Research , 15 Cotswold Road , Sutton , Surrey SM2 5NG , United Kingdom.

Macromolecule Content

Total Structure Weight: 35.35 kDa
Atom Count: 2,517
Modelled Residue Count: 296
Deposited Residue Count: 301
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Activin receptor type-1	A	301	Homo sapiens	Mutation(s): 1 Gene Names: ACVR1, ACVRLK2 EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q04771 (Homo sapiens) Explore Q04771 Go to UniProtKB: Q04771
PHAROS: Q04771 GTEx: ENSG00000115170
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q04771
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
EUN (Subject of Investigation/LOI) Query on EUN Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	2,5-dimethyl-6-quinolin-4-yl-3~{H}-quinazolin-4-one C₁₉ H₁₅ N₃ O CNEUJSQUCXSRDD-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A]	C [auth A], D [auth A], E [auth A], F [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A]	G [auth A], H [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain G [auth A] Focus chain H [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
EUN	BindingDB: 6GIP	Kd: 640 (nM) from 1 assay(s)
	BindingDB: 6GIP	IC50: 42 (nM) from 1 assay(s)
	Binding MOAD: 6GIP	IC50: 42 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.17 Å
R-Value Free: 0.239
R-Value Work: 0.195
Space Group: P 3₂ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 66.849	α = 90
b = 66.849	β = 90
c = 139.932	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
iMOSFLM	data reduction
Aimless	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-05-23

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2018-05-23
Type: Initial release
Version 1.1: 2018-08-22
Changes: Data collection, Database references
Version 1.2: 2018-09-05
Changes: Data collection, Database references
Version 1.3: 2024-01-17
Changes: Data collection, Database references, Refinement description