7C3G

Crystal structure of human ALK2 kinase domain with R206H mutation in complex with a bicyclic pyrazole inhibitor RK-73134

PDB DOI: https://doi.org/10.2210/pdb7C3G/pdb

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

Deposited: 2020-05-12 Released: 2021-03-03
Deposition Author(s): Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.227
R-Value Work: 0.185

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.

Yamamoto, H., Sakai, N., Ohte, S., Sato, T., Sekimata, K., Matsumoto, T., Nakamura, K., Watanabe, H., Mishima-Tsumagari, C., Tanaka, A., Hashizume, Y., Honma, T., Katagiri, T., Miyazono, K., Tomoda, H., Shirouzu, M., Koyama, H.

(2021) Bioorg Med Chem Lett 38: 127858-127858

PubMed: 33609658 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2021.127858
Primary Citation of Related Structures:
7C3G

PubMed Abstract:
Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.

Organizational Affiliation

Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

Macromolecule Content

Total Structure Weight: 71.88 kDa
Atom Count: 5,335
Modelled Residue Count: 586
Deposited Residue Count: 602
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, B	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
FH0 (Subject of Investigation/LOI) Query on FH0 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain O [auth B] MOL2 format, chain C [auth A] MOL2 format, chain O [auth B] mmCIF format, chain C [auth A] mmCIF format, chain O [auth B]	C [auth A], O [auth B]	~{N}-[4-(4-methylpiperazin-1-yl)phenyl]-4-(2-pyridin-3-yl-6,7-dihydro-4~{H}-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyrimidin-2-amine C₂₆ H₂₈ N₈ O OCSGNUMYNBZDDW-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain O [auth B] Interactions & Density Focus chain C [auth A] Focus chain O [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain N [auth A] SDF format, chain P [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] SDF format, chain V [auth B] SDF format, chain W [auth B] SDF format, chain X [auth B] SDF format, chain Y [auth B] SDF format, chain M [auth A] MOL2 format, chain D [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain N [auth A] MOL2 format, chain P [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] MOL2 format, chain V [auth B] MOL2 format, chain W [auth B] MOL2 format, chain X [auth B] MOL2 format, chain Y [auth B] MOL2 format, chain M [auth A] mmCIF format, chain D [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain N [auth A] mmCIF format, chain P [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B] mmCIF format, chain V [auth B] mmCIF format, chain W [auth B] mmCIF format, chain X [auth B] mmCIF format, chain Y [auth B] mmCIF format, chain M [auth A]	D [auth A] G [auth A] H [auth A] I [auth A] J [auth A] D [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A], N [auth A], P [auth B], S [auth B], T [auth B], U [auth B], V [auth B], W [auth B], X [auth B], Y [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain P [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth B] Focus chain X [auth B] Focus chain Y [auth B] Interactions & Density Focus chain D [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain P [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth B] Focus chain X [auth B] Focus chain Y [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain F [auth A] mmCIF format, chain E [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain F [auth A]	E [auth A], F [auth A], Q [auth B], R [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain Q [auth B] Focus chain R [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain Q [auth B] Focus chain R [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
FH0	BindingDB: 7C3G	IC50: 25 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.227
R-Value Work: 0.185
Space Group: P 2₁ 2₁ 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 84.34	α = 90
b = 140.259	β = 90
c = 59.758	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
XDS	data scaling
MOLREP	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2021-03-03

Deposition Author(s):

Sakai, N.

Mishima-Tsumagari, C.

Matsumoto, T.

Shirouzu, M.

Revision History (Full details and data files)

Version 1.0: 2021-03-03
Type: Initial release
Version 1.1: 2021-03-10
Changes: Database references
Version 1.2: 2023-11-29
Changes: Data collection, Database references, Derived calculations, Refinement description