3Q4U

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

Summary for 3Q4U

• Entry DOI: 10.2210/pdb3q4u/pdb
• Related: 3MTF 3OOM
• Descriptor: Activin receptor type-1, 4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: structural genomics consortium, sgc, protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: Q04771
• Total number of polymer chains: 4
• Total formula weight: 142914.61

Authors

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) (deposition date: 2010-12-24, release date: 2011-02-09, Last modification date: 2024-10-16)

Primary citation

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.
A new class of small molecule inhibitor of BMP signaling.
Plos One, 8:e62721-e62721, 2013

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.

PubMed: 23646137
DOI: 10.1371/journal.pone.0062721

Experimental method

X-RAY DIFFRACTION (1.82 Å)