View source for 6acr


==Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-59638==
<StructureSection load='6acr' size='340' side='right'caption='[[6acr]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6acr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ACR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ACR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9TO:N-(4-methoxyphenyl)-4-[3-(pyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine'>9TO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6acr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6acr OCA], [https://pdbe.org/6acr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6acr RCSB], [https://www.ebi.ac.uk/pdbsum/6acr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6acr ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ACVR1_HUMAN ACVR1_HUMAN] Fibrodysplasia ossificans progressiva. Defects in ACVR1 are a cause of fibrodysplasia ossificans progressiva (FOP) [MIM:[https://omim.org/entry/135100 135100]. FOP is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification in FOP begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to extra-articular ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible.<ref>PMID:16642017</ref> <ref>PMID:19085907</ref> <ref>PMID:19330033</ref> 
== Function ==
[https://www.uniprot.org/uniprot/ACVR1_HUMAN ACVR1_HUMAN] On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity).
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== Publication Abstract from PubMed ==
Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.

Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).,Sekimata K, Sato T, Sakai N, Watanabe H, Mishima-Tsumagari C, Taguri T, Matsumoto T, Fujii Y, Handa N, Honma T, Tanaka A, Shirouzu M, Yokoyama S, Miyazono K, Hashizume Y, Koyama H Chem Pharm Bull (Tokyo). 2019;67(3):224-235. doi: 10.1248/cpb.c18-00598. PMID:30828000<ref>PMID:30828000</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6acr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Matsumoto T]]
[[Category: Mishima-Tsumagari C]]
[[Category: Sakai N]]
[[Category: Shirouzu M]]