3mtf

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{{STRUCTURE_3mtf| PDB=3mtf | SCENE= }}
 
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===Crystal structure of the ACVR1 kinase in complex with a 2-aminopyridine inhibitor===
 
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==Disease==
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==Crystal structure of the ACVR1 kinase in complex with a 2-aminopyridine inhibitor==
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[[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>
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<StructureSection load='3mtf' size='340' side='right'caption='[[3mtf]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3mtf]] 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=3MTF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MTF FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A3F:3-[6-AMINO-5-(3,4,5-TRIMETHOXYPHENYL)PYRIDIN-3-YL]PHENOL'>A3F</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mtf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mtf OCA], [https://pdbe.org/3mtf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mtf RCSB], [https://www.ebi.ac.uk/pdbsum/3mtf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mtf ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mt/3mtf_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3mtf ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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-beta 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.
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==Function==
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A new class of small molecule inhibitor of BMP signaling.,Sanvitale CE, Kerr G, Chaikuad A, Ramel MC, Mohedas AH, Reichert S, Wang Y, Triffitt JT, Cuny GD, Yu PB, Hill CS, Bullock AN PLoS One. 2013 Apr 30;8(4):e62721. doi: 10.1371/journal.pone.0062721. Print 2013. PMID:23646137<ref>PMID:23646137</ref>
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[[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).
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3mtf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MTF OCA].
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</div>
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<div class="pdbe-citations 3mtf" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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<references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Receptor protein serine/threonine kinase]]
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[[Category: Large Structures]]
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[[Category: Alfano, I.]]
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[[Category: Alfano I]]
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[[Category: Arrowsmith, C H.]]
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[[Category: Arrowsmith CH]]
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[[Category: Bountra, C.]]
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[[Category: Bountra C]]
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[[Category: Bullock, A.]]
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[[Category: Bullock A]]
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[[Category: Canning, P.]]
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[[Category: Canning P]]
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[[Category: Chaikuad, A.]]
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[[Category: Chaikuad A]]
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[[Category: Cooper, C.]]
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[[Category: Cooper C]]
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[[Category: Daga, N.]]
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[[Category: Daga N]]
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[[Category: Delft, F von.]]
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[[Category: Edwards AM]]
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[[Category: Edwards, A M.]]
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[[Category: Knapp S]]
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[[Category: Knapp, S.]]
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[[Category: Krojer T]]
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[[Category: Krojer, T.]]
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[[Category: Mahajan P]]
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[[Category: Mahajan, P.]]
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[[Category: Petrie K]]
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[[Category: Petrie, K.]]
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[[Category: Sanvitale C]]
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[[Category: SGC, Structural Genomics Consortium.]]
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[[Category: Vollmar M]]
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[[Category: Sanvitale, C.]]
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[[Category: Weigelt J]]
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[[Category: Vollmar, M.]]
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[[Category: Von Delft F]]
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[[Category: Weigelt, J.]]
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[[Category: Protein kinase]]
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[[Category: Sgc]]
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[[Category: Structural genomic]]
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[[Category: Structural genomics consortium]]
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[[Category: Transferase]]
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Current revision

Crystal structure of the ACVR1 kinase in complex with a 2-aminopyridine inhibitor

PDB ID 3mtf

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