6jux - Revision history

OCA at 10:20, 22 November 2023

OCA — Wed, 22 Nov 2023 10:20:15 GMT

←Older revision		Revision as of 10:20, 22 November 2023
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	<StructureSection load='6jux' size='340' side='right'caption='[[6jux]], [[Resolution\|resolution]] 1.75Å' scene=''>		<StructureSection load='6jux' size='340' side='right'caption='[[6jux]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6jux]] is a 1 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=6JUX OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6JUX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jux]] is a 1 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=6JUX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JUX FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C9U:4-(1-ethyl-3-pyridin-3-yl-pyrazol-4-yl)-~{N}-(4-piperazin-1-ylphenyl)pyrimidin-2-amine'>C9U</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]] 1.75Å</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=C9U:4-(1-ethyl-3-pyridin-3-yl-pyrazol-4-yl)-~{N}-(4-piperazin-1-ylphenyl)pyrimidin-2-amine'>C9U</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=6jux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jux OCA], [https://pdbe.org/6jux PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jux RCSB], [https://www.ebi.ac.uk/pdbsum/6jux PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jux 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=6jux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jux OCA], [~~http~~://pdbe.org/6jux PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6jux RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6jux PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6jux 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).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 6jux" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6jux" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Activin receptor\|Activin receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[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: Kinase]]~~	+
-	~~[[Category: Signaling protein-inhibitor complex~~]]	+

OCA at 11:19, 22 July 2020

OCA — Wed, 22 Jul 2020 11:19:13 GMT

←Older revision		Revision as of 11:19, 22 July 2020
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	==Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-71807==		==Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-71807==
-	<StructureSection load='6jux' size='340' side='right'caption='[[6jux]]' scene=''>	+	<StructureSection load='6jux' size='340' side='right'caption='[[6jux]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JUX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JUX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jux]] is a 1 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=6JUX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JUX FirstGlance]. <br>
-	</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=6jux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jux OCA], [http://pdbe.org/6jux PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jux RCSB], [http://www.ebi.ac.uk/pdbsum/6jux PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jux ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C9U:4-(1-ethyl-3-pyridin-3-yl-pyrazol-4-yl)-~{N}-(4-piperazin-1-ylphenyl)pyrimidin-2-amine'>C9U</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='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'>[http://proteopedia.org/fgij/fg.htm?mol=6jux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jux OCA], [http://pdbe.org/6jux PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jux RCSB], [http://www.ebi.ac.uk/pdbsum/6jux PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jux ProSAT]</span></td></tr>
	</table>		</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>
		+	== 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).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Fibrodysplasia ossificans progressiva (FOP) is a rare but severe genetic disorder in which acute inflammation elicits progressive heterotopic ossification in the muscles, tendons, and ligaments. Classic FOP is caused by the R206H mutation in ALK2/ACVR1. While several activin receptor-like kinase 2 (ALK2) inhibitors were found to be efficacious in animal models of FOP, most of the ALK2 (R206H) inhibitors lacked sufficient oral bioavailability for efficacy. Previously, the synthesis of a series of novel bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitors that achieved both substantial potency and an improved ADMET profile was reported. In the present study, the detailed procedure of the in silico approach employed to identify the initial bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitor RK-59638 and the analysis of the ALK2 (R206H) RK-59638 complex structure to guide the synthetic optimization of the chemical series, obtaining RK-71807 showing improved potency and metabolic stability, were described. According to the initial in silico screening, the screening efficiencies and chemical diversity of the hit compounds of both ligand-based and structure-based methods were evaluated. Then, X-ray structures of ALK2 (R206H) and the inhibitors were analyzed to assess the structure-activity relationships of the synthesized compounds. The 3D-RISM analysis indicated the existence of the additional hydrogen bond via water molecules restricting the attachment point in the pyrazole scaffold. The quantum mechanics calculation of the newly determined ALK2 (R206H) RK-71807 complex structure using a fragment molecular orbital method and pair interaction energy decomposition analysis was employed to evaluate the interaction energies between the inhibitor and each of the amino acid residues and decompose them to electrostatic, exchange-repulsion, and charge transfer energies. The pattern of decomposed interaction energies was then compared to that formed by RK-59638 and LDN-193189 to investigate the structural basis of ALK2 (R206H) inhibition.
		+
		+	Structural Basis of Activin Receptor-Like Kinase 2 (R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for the Treatment of Fibrodysplasia Ossificans Progressiva Identified by the Integration of Ligand-Based and Structure-Based Drug Design Approaches.,Sato T, Sekimata K, Sakai N, Watanabe H, Mishima-Tsumagari C, Taguri T, Matsumoto T, Fujii Y, Handa N, Tanaka A, Shirouzu M, Yokoyama S, Hashizume Y, Miyazono K, Koyama H, Honma T ACS Omega. 2020 May 12;5(20):11411-11423. doi: 10.1021/acsomega.9b04245., eCollection 2020 May 26. PMID:32478230<ref>PMID:32478230</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6jux" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Activin receptor\|Activin receptor]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Matsumoto T]]	+	[[Category: Receptor protein serine/threonine kinase]]
-	[[Category: Mishima-Tsumagari C]]	+	[[Category: Matsumoto, T]]
-	[[Category: Sakai N]]	+	[[Category: Mishima-Tsumagari, C]]
-	[[Category: Shirouzu M]]	+	[[Category: Sakai, N]]
		+	[[Category: Shirouzu, M]]
		+	[[Category: Kinase]]
		+	[[Category: Signaling protein-inhibitor complex]]

OCA at 06:51, 15 April 2020

OCA — Wed, 15 Apr 2020 06:51:01 GMT

←Older revision		Revision as of 06:51, 15 April 2020
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-	'''Unreleased structure'''

-	~~The entry 6jux is ON HOLD until Paper Publication~~	+	==Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-71807==
-		+	<StructureSection load='6jux' size='340' side='right'caption='[[6jux]]' scene=''>
-	~~Authors: Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JUX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JUX FirstGlance]. <br>
-	~~Description:~~ Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-71807	+	</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=6jux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jux OCA], [http://pdbe.org/6jux PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jux RCSB], [http://www.ebi.ac.uk/pdbsum/6jux PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jux ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Sakai~~, N]]	+	__TOC__
-	[[Category: Matsumoto, T]]	+	</StructureSection>
-	[[Category: Mishima-Tsumagari, C]]	+	[[Category: Large Structures]]
-	[[Category: Shirouzu, M]]	+	[[Category: Matsumoto T]]
		+	[[Category: Mishima-Tsumagari C]]
		+	[[Category: Sakai N]]
		+	[[Category: Shirouzu M]]

OCA at 06:55, 1 May 2019

OCA — Wed, 01 May 2019 06:55:19 GMT

←Older revision		Revision as of 06:55, 1 May 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6jux is ON HOLD	+	The entry 6jux is ON HOLD until Paper Publication

	Authors: Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M.		Authors: Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M.
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	[[Category: Sakai, N]]		[[Category: Sakai, N]]
	[[Category: Matsumoto, T]]		[[Category: Matsumoto, T]]
-	[[Category: Shirouzu, M]]
	[[Category: Mishima-Tsumagari, C]]		[[Category: Mishima-Tsumagari, C]]
		+	[[Category: Shirouzu, M]]

OCA: Protected "6jux" [edit=sysop:move=sysop]

OCA — Wed, 24 Apr 2019 04:46:20 GMT

Protected "6jux" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:46, 24 April 2019

OCA: New page: '''Unreleased structure''' The entry 6jux is ON HOLD Authors: Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M. Description: Crystal structure of human ALK2 kinase domain w...

OCA — Wed, 24 Apr 2019 04:46:18 GMT

New page: '''Unreleased structure''' The entry 6jux is ON HOLD Authors: Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M. Description: Crystal structure of human ALK2 kinase domain w...

New page

'''Unreleased structure'''

The entry 6jux is ON HOLD

Authors: Sakai, N., Mishima-Tsumagari, C., Matsumoto, T., Shirouzu, M.

Description: Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-71807
[[Category: Unreleased Structures]]
[[Category: Sakai, N]]
[[Category: Matsumoto, T]]
[[Category: Shirouzu, M]]
[[Category: Mishima-Tsumagari, C]]