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| | ==Crystal structure of the ACVR1 kinase in complex with a 2-aminopyridine inhibitor== | | ==Crystal structure of the ACVR1 kinase in complex with a 2-aminopyridine inhibitor== |
| - | <StructureSection load='3mtf' size='340' side='right' caption='[[3mtf]], [[Resolution|resolution]] 2.15Å' scene=''> | + | <StructureSection load='3mtf' size='340' side='right'caption='[[3mtf]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3mtf]] is a 2 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=3MTF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MTF FirstGlance]. <br> | + | <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> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15Å</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='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> |
| - | <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'>[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> |
| - | <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=3mtf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mtf OCA], [http://pdbe.org/3mtf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mtf RCSB], [http://www.ebi.ac.uk/pdbsum/3mtf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mtf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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> | + | [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 == | | == 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). | + | [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). |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Receptor protein serine/threonine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Alfano, I]] | + | [[Category: Alfano I]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Bullock, A]] | + | [[Category: Bullock A]] |
| - | [[Category: Canning, P]] | + | [[Category: Canning P]] |
| - | [[Category: Chaikuad, A]] | + | [[Category: Chaikuad A]] |
| - | [[Category: Cooper, C]] | + | [[Category: Cooper C]] |
| - | [[Category: Daga, N]] | + | [[Category: Daga N]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Edwards AM]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Knapp S]] |
| - | [[Category: Knapp, S]] | + | [[Category: Krojer T]] |
| - | [[Category: Krojer, T]] | + | [[Category: Mahajan P]] |
| - | [[Category: Mahajan, P]] | + | [[Category: Petrie K]] |
| - | [[Category: Petrie, K]] | + | [[Category: Sanvitale C]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Vollmar M]] |
| - | [[Category: Sanvitale, C]] | + | [[Category: Weigelt J]] |
| - | [[Category: Vollmar, M]] | + | [[Category: Von Delft F]] |
| - | [[Category: Weigelt, J]] | + | |
| - | [[Category: Protein kinase]] | + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
ACVR1_HUMAN Fibrodysplasia ossificans progressiva. Defects in ACVR1 are a cause of fibrodysplasia ossificans progressiva (FOP) [MIM: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.[1] [2] [3]
Function
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).
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May;38(5):525-7. Epub 2006 Apr 23. PMID:16642017 doi:ng1783
- ↑ Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Koster B, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009 Mar;30(3):379-90. doi: 10.1002/humu.20868. PMID:19085907 doi:10.1002/humu.20868
- ↑ Petrie KA, Lee WH, Bullock AN, Pointon JJ, Smith R, Russell RG, Brown MA, Wordsworth BP, Triffitt JT. Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PLoS One. 2009;4(3):e5005. doi: 10.1371/journal.pone.0005005. Epub 2009 Mar 30. PMID:19330033 doi:10.1371/journal.pone.0005005
- ↑ Sanvitale CE, Kerr G, Chaikuad A, Ramel MC, Mohedas AH, Reichert S, Wang Y, Triffitt JT, Cuny GD, Yu PB, Hill CS, Bullock AN. A new class of small molecule inhibitor of BMP signaling. PLoS One. 2013 Apr 30;8(4):e62721. doi: 10.1371/journal.pone.0062721. Print 2013. PMID:23646137 doi:http://dx.doi.org/10.1371/journal.pone.0062721
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