6zgc

From Proteopedia

(Difference between revisions)

Revision as of 13:49, 24 January 2024

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound Saracatinib (AZD0530)

Structural highlights

6zgc is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.67Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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).

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^[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
↑ 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. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight. 2021 Apr 22;6(8). pii: 95042. doi: 10.1172/jci.insight.95042. PMID:33705358 doi:http://dx.doi.org/10.1172/jci.insight.95042

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6zgc"

@@ Line 3: / Line 3: @@
 <StructureSection load='6zgc' size='340' side='right'caption='[[6zgc]], [[Resolution|resolution]] 2.67&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<table><tr><td colspan='2'>[[6zgc]] is a 4 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=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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.67&#8491;</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='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='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>
 == 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>
+[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).
+[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 ==
@@ Line 26: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Receptor protein serine/threonine kinase]]
+[[Category: Arrowsmith CH]]
-[[Category: Arrowsmith, C H]]
+[[Category: Bountra C]]
-[[Category: Bartual, S Galan]]
+[[Category: Bullock AN]]
-[[Category: Bountra, C]]
+[[Category: Burgess-Brown N]]
-[[Category: Bullock, A N]]
+[[Category: Edwards AM]]
-[[Category: Burgess-Brown, N]]
+[[Category: Galan Bartual S]]
-[[Category: Delft, F von]]
+[[Category: Williams EP]]
-[[Category: Edwards, A M]]
+[[Category: Von Delft F]]
-[[Category: Williams, E P]]
-[[Category: Bmp]]
-[[Category: Inhibitor complex. kinase. type i receptor]]
-[[Category: Signaling protein]]
-[[Category: Signalling]]

6zgc

From Proteopedia

Revision as of 13:49, 24 January 2024

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound Saracatinib (AZD0530)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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