6zgc
From Proteopedia
(Difference between revisions)
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==Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound Saracatinib (AZD0530)== | ==Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound Saracatinib (AZD0530)== | ||
| - | <StructureSection load='6zgc' size='340' side='right'caption='[[6zgc]]' scene=''> | + | <StructureSection load='6zgc' size='340' side='right'caption='[[6zgc]], [[Resolution|resolution]] 2.67Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGC OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6zgc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZGC FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H8H:N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE'>H8H</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACVR1 ([https://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'>[https://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6zgc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgc OCA], [https://pdbe.org/6zgc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zgc RCSB], [https://www.ebi.ac.uk/pdbsum/6zgc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgc ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-beta signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition. | ||
| + | |||
| + | Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.,Williams E, Bagarova J, Kerr G, Xia DD, Place ES, Dey D, Shen Y, Bocobo GA, Mohedas AH, Huang X, Sanderson PE, Lee A, Zheng W, Economides AN, Smith JC, Yu PB, Bullock AN JCI Insight. 2021 Apr 22;6(8). pii: 95042. doi: 10.1172/jci.insight.95042. PMID:33705358<ref>PMID:33705358</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6zgc" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Arrowsmith | + | [[Category: Receptor protein serine/threonine kinase]] |
| - | [[Category: Bountra C]] | + | [[Category: Arrowsmith, C H]] |
| - | [[Category: Bullock | + | [[Category: Bartual, S Galan]] |
| - | [[Category: Burgess-Brown N]] | + | [[Category: Bountra, C]] |
| - | [[Category: | + | [[Category: Bullock, A N]] |
| - | [[Category: | + | [[Category: Burgess-Brown, N]] |
| - | [[Category: Williams | + | [[Category: Delft, F von]] |
| - | [[Category: | + | [[Category: Edwards, A M]] |
| + | [[Category: Williams, E P]] | ||
| + | [[Category: Bmp]] | ||
| + | [[Category: Inhibitor complex. kinase. type i receptor]] | ||
| + | [[Category: Signaling protein]] | ||
| + | [[Category: Signalling]] | ||
Revision as of 09:25, 26 May 2021
Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound Saracatinib (AZD0530)
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