View source for 6t6d


==Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2149==
<StructureSection load='6t6d' size='340' side='right'caption='[[6t6d]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6t6d]] is a 4 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=6T6D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T6D 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]] 2.56&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MM8:2-methoxy-4-[4-methyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]benzamide'>MM8</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=6t6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t6d OCA], [https://pdbe.org/6t6d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t6d RCSB], [https://www.ebi.ac.uk/pdbsum/6t6d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t6d 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).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-betaR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.,Ensan D, Smil D, Zepeda-Velazquez CA, Panagopoulos D, Wong JF, Williams EP, Adamson R, Bullock AN, Kiyota T, Aman A, Roberts OG, Edwards AM, O'Meara JA, Isaac MB, Al-Awar R J Med Chem. 2020 May 5. doi: 10.1021/acs.jmedchem.0c00395. PMID:32369358<ref>PMID:32369358</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6t6d" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adamson RJ]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Bullock AN]]
[[Category: Burgess-Brown N]]
[[Category: Edwards AM]]
[[Category: Smil D]]
[[Category: Williams EP]]
[[Category: Von Delft F]]