6i1s

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(New page: '''Unreleased structure''' The entry 6i1s is ON HOLD until Paper Publication Authors: Williams, E.P., Pinkas, D.M., Fortin, J., Newman, J.A., Bradshaw, W.J., Mahajan, P., Kupinska, K., ...)
Current revision (11:44, 24 January 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 6i1s is ON HOLD until Paper Publication
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==Crystal structure of the ACVR1 (ALK2) kinase in complex with FKBP12 and the inhibitor E6201==
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<StructureSection load='6i1s' size='340' side='right'caption='[[6i1s]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6i1s]] 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=6I1S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I1S 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]] 1.52&#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=E26:(4~{S},5~{R},6~{Z},9~{S},10~{S},12~{E})-16-(ethylamino)-4,5-dimethyl-9,10,18-tris(oxidanyl)-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione'>E26</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6i1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i1s OCA], [https://pdbe.org/6i1s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i1s RCSB], [https://www.ebi.ac.uk/pdbsum/6i1s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i1s 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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1(G328V) arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b(K27M) and Pik3ca(H1047R) to generate high-grade diffuse gliomas. Mechanistically, Acvr1(G328V) upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.
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Authors: Williams, E.P., Pinkas, D.M., Fortin, J., Newman, J.A., Bradshaw, W.J., Mahajan, P., Kupinska, K., Burgess-Brown, N., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Bullock, A.N.
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Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.,Fortin J, Tian R, Zarrabi I, Hill G, Williams E, Sanchez-Duffhues G, Thorikay M, Ramachandran P, Siddaway R, Wong JF, Wu A, Apuzzo LN, Haight J, You-Ten A, Snow BE, Wakeham A, Goldhamer DJ, Schramek D, Bullock AN, Dijke PT, Hawkins C, Mak TW Cancer Cell. 2020 Mar 16;37(3):308-323.e12. doi: 10.1016/j.ccell.2020.02.002., Epub 2020 Mar 5. PMID:32142668<ref>PMID:32142668</ref>
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Description: Crystal structure of the ACVR1 (ALK2) kinase in complex with FKBP12 and the inhibitor E6201
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Mahajan, P]]
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<div class="pdbe-citations 6i1s" style="background-color:#fffaf0;"></div>
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[[Category: Pinkas, D.M]]
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[[Category: Edwards, A.M]]
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==See Also==
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[[Category: Williams, E.P]]
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*[[FKBP 3D structures|FKBP 3D structures]]
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[[Category: Arrowsmith, C.H]]
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== References ==
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[[Category: Burgess-Brown, N]]
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<references/>
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[[Category: Bradshaw, W.J]]
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__TOC__
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[[Category: Newman, J.A]]
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</StructureSection>
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[[Category: Von Delft, F]]
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[[Category: Homo sapiens]]
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[[Category: Fortin, J]]
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[[Category: Large Structures]]
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[[Category: Bountra, C]]
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[[Category: Arrowsmith CH]]
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[[Category: Bullock, A.N]]
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[[Category: Bountra C]]
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[[Category: Kupinska, K]]
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[[Category: Bradshaw WJ]]
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[[Category: Bullock AN]]
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[[Category: Burgess-Brown N]]
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[[Category: Edwards AM]]
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[[Category: Fortin J]]
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[[Category: Kupinska K]]
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[[Category: Mahajan P]]
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[[Category: Newman JA]]
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[[Category: Pinkas DM]]
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[[Category: Williams EP]]
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[[Category: Von Delft F]]

Current revision

Crystal structure of the ACVR1 (ALK2) kinase in complex with FKBP12 and the inhibitor E6201

PDB ID 6i1s

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