View source for 6gip


==Crystal structure of the ACVR1 (ALK2) kinase in complex with a Quinazolinone based ALK2 inhibitor with a 2, 5-dimethyl core.==
<StructureSection load='6gip' size='340' side='right' caption='[[6gip]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6gip]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GIP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GIP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EUN:2,5-dimethyl-6-quinolin-4-yl-3~{H}-quinazolin-4-one'>EUN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACVR1, ACVRLK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6gip FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gip OCA], [http://pdbe.org/6gip PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gip RCSB], [http://www.ebi.ac.uk/pdbsum/6gip PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gip ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/ACVR1_HUMAN ACVR1_HUMAN]] Fibrodysplasia ossificans progressiva. Defects in ACVR1 are a cause of fibrodysplasia ossificans progressiva (FOP) [MIM:[http://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 ==
[[http://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 ==
Structure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.

Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.,Hudson L, Mui J, Vazquez S, Carvalho DM, Williams E, Jones C, Bullock AN, Hoelder S J Med Chem. 2018 Aug 7. doi: 10.1021/acs.jmedchem.8b00782. PMID:30085668<ref>PMID:30085668</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6gip" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Receptor protein serine/threonine kinase]]
[[Category: Arrowsmith, C H]]
[[Category: Bezerra, G A]]
[[Category: Bountra, C]]
[[Category: Bullock, A N]]
[[Category: Burgess-Brown, N]]
[[Category: Chen, Z]]
[[Category: Delft, F von]]
[[Category: Edwards, A M]]
[[Category: Hoelder, S]]
[[Category: Hudson, L]]
[[Category: Kupinska, K]]
[[Category: Mahajan, P]]
[[Category: Mathea, S]]
[[Category: Sorrell, F]]
[[Category: Williams, E]]
[[Category: Bmp]]
[[Category: Inhibitor]]
[[Category: Kinase]]
[[Category: Signaling protein]]
[[Category: Signalling]]