5my4 - Revision history

OCA at 17:53, 8 November 2023

OCA — Wed, 08 Nov 2023 17:53:40 GMT

←Older revision		Revision as of 17:53, 8 November 2023
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	<StructureSection load='5my4' size='340' side='right'caption='[[5my4]], [[Resolution\|resolution]] 2.21Å' scene=''>		<StructureSection load='5my4' size='340' side='right'caption='[[5my4]], [[Resolution\|resolution]] 2.21Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5my4]] is a 3 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Lk3_transgenic_mice Lk3 transgenic mice~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MY4 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5MY4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5my4]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MY4 FirstGlance]. <br>
-	</td></tr><tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non~~-~~Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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]] 2.211Å</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=5my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5my4 OCA], [~~http~~://pdbe.org/5my4 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5my4 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5my4 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5my4 ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=5my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5my4 OCA], [https://pdbe.org/5my4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5my4 RCSB], [https://www.ebi.ac.uk/pdbsum/5my4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5my4 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:[https://omim.org/entry/104300 104300]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.<ref>PMID:8476439</ref> <ref>PMID:15201367</ref> <ref>PMID:1671712</ref> <ref>PMID:1908231</ref> <ref>PMID:1678058</ref> <ref>PMID:1944558</ref> <ref>PMID:1925564</ref> <ref>PMID:1415269</ref> <ref>PMID:1303239</ref> <ref>PMID:1302033</ref> <ref>PMID:1303275</ref> <ref>PMID:8267572</ref> <ref>PMID:8290042</ref> <ref>PMID:8577393</ref> <ref>PMID:9328472</ref> <ref>PMID:9754958</ref> <ref>PMID:10097173</ref> <ref>PMID:10631141</ref> <ref>PMID:10665499</ref> <ref>PMID:10867787</ref> <ref>PMID:11063718</ref> <ref>PMID:11311152</ref> <ref>PMID:11528419</ref> <ref>PMID:12034808</ref> <ref>PMID:15365148</ref> <ref>PMID:15668448</ref> Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:[https://omim.org/entry/605714 605714]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.<ref>PMID:10821838</ref> <ref>PMID:2111584</ref> <ref>PMID:11409420</ref> <ref>PMID:12654973</ref> <ref>PMID:16178030</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Lk3 transgenic mice~~]]	+	[[Category: Mus musculus]]
-	[[Category: Parthier, C]]	+	[[Category: Parthier C]]
-	[[Category: Piechotta, A]]	+	[[Category: Piechotta A]]
-	[[Category: Stubbs~~, M T]]~~	+	[[Category: Stubbs MT]]
-	~~[[Category: Alzheimer's disease]]~~	+
-	~~[[Category: Fibrillation]]~~	+
-	~~[[Category: Immune system]]~~	+
-	~~[[Category: Monoclonal antibody]]~~	+
-	~~[[Category: Pyroglutamate abeta~~]]	+

OCA at 07:47, 11 March 2020

OCA — Wed, 11 Mar 2020 07:47:09 GMT

←Older revision		Revision as of 07:47, 11 March 2020
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	==Structure of Pyroglutamate-Abeta-specific Fab c#17 in complex with human Abeta-pE3-12PEGb==		==Structure of Pyroglutamate-Abeta-specific Fab c#17 in complex with human Abeta-pE3-12PEGb==
-	<StructureSection load='5my4' size='340' side='right' caption='[[5my4]], [[Resolution\|resolution]] 2.21Å' scene=''>	+	<StructureSection load='5my4' size='340' side='right'caption='[[5my4]], [[Resolution\|resolution]] 2.21Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5my4]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MY4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5my4]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MY4 FirstGlance]. <br>
	</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>		</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=5my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5my4 OCA], [http://pdbe.org/5my4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5my4 RCSB], [http://www.ebi.ac.uk/pdbsum/5my4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5my4 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=5my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5my4 OCA], [http://pdbe.org/5my4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5my4 RCSB], [http://www.ebi.ac.uk/pdbsum/5my4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5my4 ProSAT]</span></td></tr>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Lk3 transgenic mice]]
	[[Category: Parthier, C]]		[[Category: Parthier, C]]
	[[Category: Piechotta, A]]		[[Category: Piechotta, A]]

OCA at 09:11, 9 August 2017

OCA — Wed, 09 Aug 2017 09:11:45 GMT

←Older revision		Revision as of 09:11, 9 August 2017
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-	'''Unreleased structure'''

-	~~The entry~~ 5my4 is ~~ON HOLD until Paper~~ Publication	+	==Structure of Pyroglutamate-Abeta-specific Fab c#17 in complex with human Abeta-pE3-12PEGb==
		+	<StructureSection load='5my4' size='340' side='right' caption='[[5my4]], [[Resolution\|resolution]] 2.21Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5my4]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MY4 FirstGlance]. <br>
		+	</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=5my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5my4 OCA], [http://pdbe.org/5my4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5my4 RCSB], [http://www.ebi.ac.uk/pdbsum/5my4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5my4 ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Alzheimer disease is associated with deposition of the amyloidogenic peptide Abeta in the brain. Passive immunization using Abeta-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified Abeta species (AbetapE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize AbetapE3 with affinities of 1-10 nm and inhibit AbetapE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in AbetapE3 oligomer-treated mice. Crystal structures of Fab-AbetapE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the AbetapE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.

-	~~Authors~~:	+	Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy.,Piechotta A, Parthier C, Kleinschmidt M, Gnoth K, Pillot T, Lues I, Demuth HU, Schilling S, Rahfeld JU, Stubbs MT J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub , 2017 Jun 16. PMID:28623233<ref>PMID:28623233</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5my4" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Parthier, C]]
		+	[[Category: Piechotta, A]]
		+	[[Category: Stubbs, M T]]
		+	[[Category: Alzheimer's disease]]
		+	[[Category: Fibrillation]]
		+	[[Category: Immune system]]
		+	[[Category: Monoclonal antibody]]
		+	[[Category: Pyroglutamate abeta]]

OCA at 11:46, 9 March 2017

OCA — Thu, 09 Mar 2017 11:46:52 GMT

←Older revision		Revision as of 11:46, 9 March 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5my4 is ON HOLD	+	The entry 5my4 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "5my4" [edit=sysop:move=sysop]

OCA — Wed, 01 Feb 2017 15:23:31 GMT

Protected "5my4" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:23, 1 February 2017

OCA: New page: '''Unreleased structure''' The entry 5my4 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 01 Feb 2017 15:23:30 GMT

New page: '''Unreleased structure''' The entry 5my4 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5my4 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]