6t6d

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2149

Structural highlights

6t6d 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 2.56Å
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

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-betaR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.,Ensan D, Smil D, Zepeda-Velazquez CA, Panagopoulos D, Wong JF, Williams EP, Adamson R, Bullock AN, Kiyota T, Aman A, Roberts OG, Edwards AM, O'Meara JA, Isaac MB, Al-Awar R J Med Chem. 2020 May 5. doi: 10.1021/acs.jmedchem.0c00395. PMID:32369358^[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
↑ Ensan D, Smil D, Zepeda-Velazquez CA, Panagopoulos D, Wong JF, Williams EP, Adamson R, Bullock AN, Kiyota T, Aman A, Roberts OG, Edwards AM, O'Meara JA, Isaac MB, Al-Awar R. Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma. J Med Chem. 2020 May 5. doi: 10.1021/acs.jmedchem.0c00395. PMID:32369358 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00395

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/6t6d"

@@ Line 3: / Line 3: @@
 <StructureSection load='6t6d' size='340' side='right'caption='[[6t6d]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6t6d]] is a 4 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=6T6D OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6T6D FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6t6d]] 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=6T6D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T6D FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MM8:2-methoxy-4-[4-methyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]benzamide'>MM8</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]] 2.56&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACVR1 ([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=MM8:2-methoxy-4-[4-methyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]benzamide'>MM8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6t6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t6d OCA], [https://pdbe.org/6t6d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t6d RCSB], [https://www.ebi.ac.uk/pdbsum/6t6d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t6d ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6t6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t6d OCA], [http://pdbe.org/6t6d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t6d RCSB], [http://www.ebi.ac.uk/pdbsum/6t6d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t6d 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 22: / Line 21: @@
 </div>
 <div class="pdbe-citations 6t6d" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Activin receptor|Activin receptor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Receptor protein serine/threonine kinase]]
+[[Category: Adamson RJ]]
-[[Category: Adamson, R J]]
+[[Category: Arrowsmith CH]]
-[[Category: Arrowsmith, C H]]
+[[Category: Bountra C]]
-[[Category: Bountra, C]]
+[[Category: Bullock AN]]
-[[Category: Bullock, A N]]
+[[Category: Burgess-Brown N]]
-[[Category: Burgess-Brown, N]]
+[[Category: Edwards AM]]
-[[Category: Delft, F von]]
+[[Category: Smil D]]
-[[Category: Edwards, A M]]
+[[Category: Williams EP]]
-[[Category: Smil, D]]
+[[Category: Von Delft F]]
-[[Category: Williams, E P]]
-[[Category: Bmp]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Signaling protein]]
-[[Category: Signalling]]

6t6d

From Proteopedia

Current revision

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2149

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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