6c6m - Revision history

OCA at 14:32, 6 March 2024

OCA — Wed, 06 Mar 2024 14:32:38 GMT

←Older revision		Revision as of 14:32, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='6c6m' size='340' side='right'caption='[[6c6m]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='6c6m' size='340' side='right'caption='[[6c6m]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6c6m]] is a 3 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=6C6M OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6C6M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6c6m]] is a 3 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=6C6M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6C6M FirstGlance]. <br>
-	</td></tr><tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>MYLK, MLCK, MLCK1, MYLK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN])</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]] 2.5Å</td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~">~~<b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>~~[~~http://en.wikipedia.org/wiki/~~[~~Myosin_light-chain~~]~~_kinase [Myosin light-chain~~] ~~kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=~~2.~~7.11.18 2.7.11.18] </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=6c6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c6m OCA], [https://pdbe.org/6c6m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c6m RCSB], [https://www.ebi.ac.uk/pdbsum/6c6m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c6m 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=6c6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c6m OCA], [~~http~~://pdbe.org/6c6m PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6c6m RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6c6m PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6c6m ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/MYLK_HUMAN MYLK_HUMAN]] Defects in MYLK are the cause of familial aortic aneurysm thoracic type 7 (AAT7) [MIM:[~~http~~://omim.org/entry/613780 613780]]. AAT7 is a disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance.<ref>PMID:21055718</ref>	+	[https://www.uniprot.org/uniprot/MYLK_HUMAN MYLK_HUMAN] Defects in MYLK are the cause of familial aortic aneurysm thoracic type 7 (AAT7) [MIM:[https://omim.org/entry/613780 613780]. AAT7 is a disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance.<ref>PMID:21055718</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/MYLK_HUMAN MYLK_HUMAN]] Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA-dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis.<ref>PMID:11113114</ref> <ref>PMID:15020676</ref> <ref>PMID:11976941</ref> <ref>PMID:15825080</ref> <ref>PMID:16723733</ref> <ref>PMID:16284075</ref> <ref>PMID:18710790</ref> <ref>PMID:18587400</ref> <ref>PMID:19826488</ref> <ref>PMID:20453870</ref> <ref>PMID:20375339</ref> <ref>PMID:20181817</ref> <ref>PMID:20139351</ref>	+	[https://www.uniprot.org/uniprot/MYLK_HUMAN MYLK_HUMAN] Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA-dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis.<ref>PMID:11113114</ref> <ref>PMID:15020676</ref> <ref>PMID:11976941</ref> <ref>PMID:15825080</ref> <ref>PMID:16723733</ref> <ref>PMID:16284075</ref> <ref>PMID:18710790</ref> <ref>PMID:18587400</ref> <ref>PMID:19826488</ref> <ref>PMID:20453870</ref> <ref>PMID:20375339</ref> <ref>PMID:20181817</ref> <ref>PMID:20139351</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.	+
-		+
-	Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis.,Graham WV, He W, Marchiando AM, Zha J, Singh G, Li HS, Biswas A, Ong MLDM, Jiang ZH, Choi W, Zuccola H, Wang Y, Griffith J, Wu J, Rosenberg HJ, Wang Y, Snapper SB, Ostrov D, Meredith SC, Miller LW, Turner JR Nat Med. 2019 Apr;25(4):690-700. doi: 10.1038/s41591-019-0393-7. Epub 2019 Apr 1. PMID:30936544<ref>PMID:30936544</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6c6m" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 28:		Line 18:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Turner, J]]	+	[[Category: Turner J]]
-	[[Category: Zuccola~~, H J]]~~	+	[[Category: Zuccola HJ]]
-	~~[[Category: Cell adhesion]]~~	+
-	~~[[Category: Igcam mlck1 ibd~~]]	+

OCA at 12:48, 25 December 2019

OCA — Wed, 25 Dec 2019 12:48:28 GMT

←Older revision		Revision as of 12:48, 25 December 2019
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 6c6m" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6c6m" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Myosin light chain kinase\|Myosin light chain kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:13, 7 August 2019

OCA — Wed, 07 Aug 2019 06:13:25 GMT

←Older revision		Revision as of 06:13, 7 August 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6c6m is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==IgCam3 of human MLCK1==
		+	<StructureSection load='6c6m' size='340' side='right'caption='[[6c6m]], [[Resolution\|resolution]] 2.50Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6c6m]] is a 3 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=6C6M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C6M FirstGlance]. <br>
		+	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MYLK, MLCK, MLCK1, MYLK1 ([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/[Myosin_light-chain]_kinase [Myosin light-chain] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.18 2.7.11.18] </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=6c6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c6m OCA], [http://pdbe.org/6c6m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c6m RCSB], [http://www.ebi.ac.uk/pdbsum/6c6m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c6m ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/MYLK_HUMAN MYLK_HUMAN]] Defects in MYLK are the cause of familial aortic aneurysm thoracic type 7 (AAT7) [MIM:[http://omim.org/entry/613780 613780]]. AAT7 is a disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance.<ref>PMID:21055718</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MYLK_HUMAN MYLK_HUMAN]] Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA-dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis.<ref>PMID:11113114</ref> <ref>PMID:15020676</ref> <ref>PMID:11976941</ref> <ref>PMID:15825080</ref> <ref>PMID:16723733</ref> <ref>PMID:16284075</ref> <ref>PMID:18710790</ref> <ref>PMID:18587400</ref> <ref>PMID:19826488</ref> <ref>PMID:20453870</ref> <ref>PMID:20375339</ref> <ref>PMID:20181817</ref> <ref>PMID:20139351</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.

-	~~Authors: Zuccola, H~~.J., ~~Turner~~, J.	+	Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis.,Graham WV, He W, Marchiando AM, Zha J, Singh G, Li HS, Biswas A, Ong MLDM, Jiang ZH, Choi W, Zuccola H, Wang Y, Griffith J, Wu J, Rosenberg HJ, Wang Y, Snapper SB, Ostrov D, Meredith SC, Miller LW, Turner JR Nat Med. 2019 Apr;25(4):690-700. doi: 10.1038/s41591-019-0393-7. Epub 2019 Apr 1. PMID:30936544<ref>PMID:30936544</ref>

-	~~Description: IgCam3~~ of ~~human MLCK1~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6c6m" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Turner, J]]		[[Category: Turner, J]]
-	[[Category: Zuccola, H.J]]	+	[[Category: Zuccola, H J]]
		+	[[Category: Cell adhesion]]
		+	[[Category: Igcam mlck1 ibd]]

OCA at 03:42, 8 March 2018

OCA — Thu, 08 Mar 2018 03:42:16 GMT

←Older revision		Revision as of 03:42, 8 March 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6c6m is ON HOLD	+	The entry 6c6m is ON HOLD until Paper Publication

	Authors: Zuccola, H.J., Turner, J.		Authors: Zuccola, H.J., Turner, J.

OCA: Protected "6c6m" [edit=sysop:move=sysop]

OCA — Wed, 24 Jan 2018 17:23:47 GMT

Protected "6c6m" [edit=sysop:move=sysop]

←Older revision

Revision as of 17:23, 24 January 2018

OCA: New page: '''Unreleased structure''' The entry 6c6m is ON HOLD Authors: Zuccola, H.J., Turner, J. Description: IgCam3 of human MLCK1 Category: Unreleased Structures Category: Turner, J [...

OCA — Wed, 24 Jan 2018 17:23:46 GMT

New page: '''Unreleased structure''' The entry 6c6m is ON HOLD Authors: Zuccola, H.J., Turner, J. Description: IgCam3 of human MLCK1 Category: Unreleased Structures Category: Turner, J [...

New page

'''Unreleased structure'''

The entry 6c6m is ON HOLD

Authors: Zuccola, H.J., Turner, J.

Description: IgCam3 of human MLCK1
[[Category: Unreleased Structures]]
[[Category: Turner, J]]
[[Category: Zuccola, H.J]]