3Q4U

Crystal structure of the ACVR1 kinase domain in complex with LDN-193189

PDB DOI: https://doi.org/10.2210/pdb3Q4U/pdb

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

Deposited: 2010-12-24 Released: 2011-02-09
Deposition Author(s): Chaikuad, A., Sanvitale, C., Cooper, C.D.O., Mahajan, P., Daga, N., Petrie, K., Alfano, I., Gileadi, O., Fedorov, O., Allerston, C.K., Krojer, T., Vollmar, M., von Delft, F., Weigelt, J., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Bullock, A., Structural Genomics Consortium (SGC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.82 ?
R-Value Free: 0.219
R-Value Work: 0.163
R-Value Observed: 0.166

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

A new class of small molecule inhibitor of BMP signaling.

Sanvitale, C.E., Kerr, G., Chaikuad, A., Ramel, M.C., Mohedas, A.H., Reichert, S., Wang, Y., Triffitt, J.T., Cuny, G.D., Yu, P.B., Hill, C.S., Bullock, A.N.

(2013) PLoS One 8: e62721-e62721

PubMed: 23646137 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1371/journal.pone.0062721
Primary Citation of Related Structures:
3MTF, 3Q4U

PubMed Abstract:
Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.

Organizational Affiliation

Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.

Macromolecule Content

Total Structure Weight: 142.91 kDa
Atom Count: 11,134
Modelled Residue Count: 1,193
Deposited Residue Count: 1,204
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Activin receptor type-1	A, B, C, D	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
LDN Query on LDN Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain M [auth B] SDF format, chain T [auth C] SDF format, chain AA [auth D] MOL2 format, chain E [auth A] MOL2 format, chain M [auth B] MOL2 format, chain T [auth C] MOL2 format, chain AA [auth D] mmCIF format, chain E [auth A] mmCIF format, chain M [auth B] mmCIF format, chain T [auth C] mmCIF format, chain AA [auth D]	AA [auth D], E [auth A], M [auth B], T [auth C]	4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline C₂₅ H₂₂ N₆ CDOVNWNANFFLFJ-UHFFFAOYSA-N		Interactions Focus chain AA [auth D] Focus chain E [auth A] Focus chain M [auth B] Focus chain T [auth C] Interactions & Density Focus chain AA [auth D] Focus chain E [auth A] Focus chain M [auth B] Focus chain T [auth C]
FLC Query on FLC Download Ideal Coordinates CCD File SDF format, chain FA [auth D] SDF format, chain GA [auth D] SDF format, chain HA [auth D] SDF format, chain K [auth A] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain X [auth C] SDF format, chain Y [auth C] SDF format, chain Z [auth C] SDF format, chain L [auth A] MOL2 format, chain FA [auth D] MOL2 format, chain GA [auth D] MOL2 format, chain HA [auth D] MOL2 format, chain K [auth A] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain X [auth C] MOL2 format, chain Y [auth C] MOL2 format, chain Z [auth C] MOL2 format, chain L [auth A] mmCIF format, chain FA [auth D] mmCIF format, chain GA [auth D] mmCIF format, chain HA [auth D] mmCIF format, chain K [auth A] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain X [auth C] mmCIF format, chain Y [auth C] mmCIF format, chain Z [auth C] mmCIF format, chain L [auth A]	FA [auth D] GA [auth D] HA [auth D] K [auth A] L [auth A] FA [auth D], GA [auth D], HA [auth D], K [auth A], L [auth A], P [auth B], Q [auth B], R [auth B], S [auth B], X [auth C], Y [auth C], Z [auth C]	CITRATE ANION C₆ H₅ O₇ KRKNYBCHXYNGOX-UHFFFAOYSA-K		Interactions Focus chain FA [auth D] Focus chain GA [auth D] Focus chain HA [auth D] Focus chain K [auth A] Focus chain L [auth A] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain X [auth C] Focus chain Y [auth C] Focus chain Z [auth C] Interactions & Density Focus chain FA [auth D] Focus chain GA [auth D] Focus chain HA [auth D] Focus chain K [auth A] Focus chain L [auth A] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain X [auth C] Focus chain Y [auth C] Focus chain Z [auth C]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain BA [auth D] SDF format, chain CA [auth D] SDF format, chain EA [auth D] SDF format, chain F [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 O [auth B] SDF format, chain U [auth C] SDF format, chain V [auth C] SDF format, chain W [auth C] SDF format, chain DA [auth D] SDF format, chain N [auth B] MOL2 format, chain BA [auth D] MOL2 format, chain CA [auth D] MOL2 format, chain EA [auth D] MOL2 format, chain F [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 O [auth B] MOL2 format, chain U [auth C] MOL2 format, chain V [auth C] MOL2 format, chain W [auth C] MOL2 format, chain DA [auth D] MOL2 format, chain N [auth B] mmCIF format, chain BA [auth D] mmCIF format, chain CA [auth D] mmCIF format, chain EA [auth D] mmCIF format, chain F [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 O [auth B] mmCIF format, chain U [auth C] mmCIF format, chain V [auth C] mmCIF format, chain W [auth C] mmCIF format, chain DA [auth D] mmCIF format, chain N [auth B]	BA [auth D] CA [auth D] DA [auth D] EA [auth D] F [auth A] BA [auth D], CA [auth D], DA [auth D], EA [auth D], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], N [auth B], O [auth B], U [auth C], V [auth C], W [auth C]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain BA [auth D] Focus chain CA [auth D] Focus chain DA [auth D] Focus chain EA [auth D] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain U [auth C] Focus chain V [auth C] Focus chain W [auth C] Interactions & Density Focus chain BA [auth D] Focus chain CA [auth D] Focus chain DA [auth D] Focus chain EA [auth D] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain U [auth C] Focus chain V [auth C] Focus chain W [auth C]

Binding Affinity Annotations
ID	Source	Binding Affinity
LDN	BindingDB: 3Q4U	IC50: min: 0.67, max: 43.3 (nM) from 6 assay(s)
LDN	BindingDB: 3Q4U	EC50: 14 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.82 ?
R-Value Free: 0.219
R-Value Work: 0.163
R-Value Observed: 0.166
Space Group: P 1 2₁ 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 83.6	α = 90
b = 98.7	β = 117.42
c = 83.85	γ = 90

Software Package:

Software Name	Purpose
GDA	data collection
PHASER	phasing
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-02-09

Deposition Author(s):

Structural Genomics Consortium (SGC)

Revision History (Full details and data files)

Version 1.0: 2011-02-09
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2014-06-18
Changes: Database references
Version 1.3: 2023-09-13
Changes: Data collection, Database references, Derived calculations, Refinement description
Version 1.4: 2024-10-16
Changes: Structure summary