OCA at 13:41, 24 January 2024

2024-01-24T13:41:38Z

←Older revision		Revision as of 13:41, 24 January 2024
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	==A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 10 in P21 space group==		==A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 10 in P21 space group==
-	<StructureSection load='6z4m' size='340' side='right'caption='[[6z4m]]' scene=''>	+	<StructureSection load='6z4m' size='340' side='right'caption='[[6z4m]], [[Resolution\|resolution]] 1.55Å' 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=6Z4M OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6Z4M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6z4m]] 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=6Z4M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z4M 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=6z4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z4m OCA], [~~http~~://pdbe.org/6z4m PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6z4m RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6z4m PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6z4m ProSAT]</span></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]] 1.55Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=Q8E:~{N}-[(6-methoxypyridin-3-yl)methyl]-2-selanyl-benzamide'>Q8E</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6z4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z4m OCA], [https://pdbe.org/6z4m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z4m RCSB], [https://www.ebi.ac.uk/pdbsum/6z4m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z4m ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/SODC_HUMAN SODC_HUMAN] Defects in SOD1 are the cause of amyotrophic lateral sclerosis type 1 (ALS1) [MIM:[https://omim.org/entry/105400 105400]. ALS1 is a familial form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of cases leading to familial forms.<ref>PMID:12963370</ref> <ref>PMID:19741096</ref> <ref>PMID:8528216</ref> <ref>PMID:8682505</ref> <ref>PMID:9541385</ref> <ref>PMID:12754496</ref> <ref>PMID:15056757</ref> <ref>PMID:18378676</ref> [:]<ref>PMID:8446170</ref> <ref>PMID:8351519</ref> <ref>PMID:8179602</ref> <ref>PMID:7980516</ref> <ref>PMID:8069312</ref> <ref>PMID:7951252</ref> <ref>PMID:7881433</ref> <ref>PMID:7836951</ref> <ref>PMID:7997024</ref> <ref>PMID:7870076</ref> <ref>PMID:7887412</ref> <ref>PMID:7795609</ref> <ref>PMID:7655468</ref> <ref>PMID:7655469</ref> <ref>PMID:7655471</ref> <ref>PMID:7700376</ref> <ref>PMID:7647793</ref> <ref>PMID:7501156</ref> <ref>PMID:7496169</ref> <ref>PMID:8938700</ref> <ref>PMID:8907321</ref> <ref>PMID:8990014</ref> <ref>PMID:9101297</ref> <ref>PMID:9455977</ref> <ref>PMID:10732812</ref> <ref>PMID:9131652</ref> <ref>PMID:10400992</ref> <ref>PMID:10430435</ref> <ref>PMID:11535232</ref> <ref>PMID:11369193</ref> <ref>PMID:12402272</ref> <ref>PMID:12145308</ref> <ref>PMID:14506936</ref> <ref>PMID:18552350</ref> <ref>PMID:18301754</ref> <ref>PMID:21247266</ref> <ref>PMID:21220647</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/SODC_HUMAN SODC_HUMAN] Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. METHODS: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. FINDING: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. INTERPRETATION: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). FUNDING: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
		+
		+	Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis.,Amporndanai K, Rogers M, Watanabe S, Yamanaka K, O'Neill PM, Hasnain SS EBioMedicine. 2020 Aug 27;59:102980. doi: 10.1016/j.ebiom.2020.102980. PMID:32862101<ref>PMID:32862101</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6z4m" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Superoxide dismutase 3D structures\|Superoxide dismutase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Amporndanai K]]		[[Category: Amporndanai K]]
	[[Category: Hasnain SS]]		[[Category: Hasnain SS]]

OCA at 09:52, 16 September 2020

2020-09-16T09:52:40Z

←Older revision		Revision as of 09:52, 16 September 2020
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-	'''Unreleased structure'''

-	~~The entry 6z4m is ON HOLD until Paper Publication~~	+	==A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 10 in P21 space group==
-		+	<StructureSection load='6z4m' size='340' side='right'caption='[[6z4m]]' scene=''>
-	~~Authors: Amporndanai, K., Hasnain, S.S.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z4M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Z4M FirstGlance]. <br>
-	~~Description:~~ A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 10 in P21 space group	+	</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=6z4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z4m OCA], [http://pdbe.org/6z4m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6z4m RCSB], [http://www.ebi.ac.uk/pdbsum/6z4m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6z4m ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Hasnain~~, S.S]]	+	__TOC__
-	[[Category: Amporndanai, K]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Amporndanai K]]
		+	[[Category: Hasnain SS]]

OCA at 04:54, 2 September 2020

2020-09-02T04:54:59Z

←Older revision		Revision as of 04:54, 2 September 2020
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	Authors: Amporndanai, K., Hasnain, S.S.		Authors: Amporndanai, K., Hasnain, S.S.

-	Description: A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 9 in P21 space group	+	Description: A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 10 in P21 space group
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Hasnain, S.S]]		[[Category: Hasnain, S.S]]
	[[Category: Amporndanai, K]]		[[Category: Amporndanai, K]]

OCA at 07:44, 22 July 2020

2020-07-22T07:44:51Z

←Older revision		Revision as of 07:44, 22 July 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6z4m is ON HOLD	+	The entry 6z4m is ON HOLD until Paper Publication

	Authors: Amporndanai, K., Hasnain, S.S.		Authors: Amporndanai, K., Hasnain, S.S.

OCA: Protected "6z4m" [edit=sysop:move=sysop]

2020-06-03T05:19:58Z

Protected "6z4m" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:19, 3 June 2020

OCA: New page: '''Unreleased structure''' The entry 6z4m is ON HOLD Authors: Amporndanai, K., Hasnain, S.S. Description: A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone...

2020-06-03T05:19:57Z

New page: '''Unreleased structure''' The entry 6z4m is ON HOLD Authors: Amporndanai, K., Hasnain, S.S. Description: A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone...

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