6acr

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-59638

Structural highlights

6acr is a 2 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 2.01Å
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

Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.

Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).,Sekimata K, Sato T, Sakai N, Watanabe H, Mishima-Tsumagari C, Taguri T, Matsumoto T, Fujii Y, Handa N, Honma T, Tanaka A, Shirouzu M, Yokoyama S, Miyazono K, Hashizume Y, Koyama H Chem Pharm Bull (Tokyo). 2019;67(3):224-235. doi: 10.1248/cpb.c18-00598. PMID:30828000^[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
↑ Sekimata K, Sato T, Sakai N, Watanabe H, Mishima-Tsumagari C, Taguri T, Matsumoto T, Fujii Y, Handa N, Honma T, Tanaka A, Shirouzu M, Yokoyama S, Miyazono K, Hashizume Y, Koyama H. Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H). Chem Pharm Bull (Tokyo). 2019;67(3):224-235. doi: 10.1248/cpb.c18-00598. PMID:30828000 doi:http://dx.doi.org/10.1248/cpb.c18-00598

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/6acr"

@@ Line 3: / Line 3: @@
 <StructureSection load='6acr' size='340' side='right'caption='[[6acr]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6acr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ACR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ACR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6acr]] 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=6ACR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ACR FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9TO:N-(4-methoxyphenyl)-4-[3-(pyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine'>9TO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.01&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9TO:N-(4-methoxyphenyl)-4-[3-(pyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine'>9TO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6acr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6acr OCA], [http://pdbe.org/6acr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6acr RCSB], [http://www.ebi.ac.uk/pdbsum/6acr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6acr ProSAT]</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=6acr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6acr OCA], [https://pdbe.org/6acr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6acr RCSB], [https://www.ebi.ac.uk/pdbsum/6acr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6acr ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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).
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Receptor protein serine/threonine kinase]]
+[[Category: Matsumoto T]]
-[[Category: Matsumoto, T]]
+[[Category: Mishima-Tsumagari C]]
-[[Category: Mishima-Tsumagari, C]]
+[[Category: Sakai N]]
-[[Category: Sakai, N]]
+[[Category: Shirouzu M]]
-[[Category: Shirouzu, M]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Signaling protein]]

6acr

From Proteopedia

Current revision

Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-59638

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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