8d3i - Revision history

OCA at 19:48, 29 May 2024

2024-05-29T19:48:23Z

←Older revision		Revision as of 19:48, 29 May 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/AIFM1_HUMAN AIFM1_HUMAN] Probable oxidoreductase that has a dual role in controlling cellular life and death; during apoptosis, it is translocated from the mitochondria to the nucleus to function as a proapoptotic factor in a caspase-independent pathway, while in normal mitochondria, it functions as an antiapoptotic factor via its oxidoreductase activity. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Interacts with EIF3G,and thereby inhibits the EIF3 machinery and protein synthesis, and activates casapse-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Binds to DNA in a sequence-independent manner.<ref>PMID:17094969</ref> <ref>PMID:19418225</ref> <ref>PMID:20362274</ref>		[https://www.uniprot.org/uniprot/AIFM1_HUMAN AIFM1_HUMAN] Probable oxidoreductase that has a dual role in controlling cellular life and death; during apoptosis, it is translocated from the mitochondria to the nucleus to function as a proapoptotic factor in a caspase-independent pathway, while in normal mitochondria, it functions as an antiapoptotic factor via its oxidoreductase activity. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Interacts with EIF3G,and thereby inhibits the EIF3 machinery and protein synthesis, and activates casapse-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Binds to DNA in a sequence-independent manner.<ref>PMID:17094969</ref> <ref>PMID:19418225</ref> <ref>PMID:20362274</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Drug discovery relies on efficient identification of small-molecule leads and their interactions with macromolecular targets. However, understanding how chemotypes impact mechanistically important conformational states often remains secondary among high-throughput discovery methods. Here, we present a conformational discovery pipeline integrating time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS) and classic fragment screening applied to allosteric states of the mitochondrial import oxidoreductase apoptosis-inducing factor (AIF). By monitoring oxidized and X-ray-reduced AIF states, TR-HT-SAXS leverages structure and kinetics to generate a multidimensional screening dataset that identifies fragment chemotypes allosterically stimulating AIF dimerization. Fragment-induced dimerization rates, quantified with time-resolved SAXS similarity analysis (k(VR)), capture structure-activity relationships (SAR) across the top-ranked 4-aminoquinoline chemotype. Crystallized AIF-aminoquinoline complexes validate TR-SAXS-guided SAR, supporting this conformational chemotype for optimization. AIF-aminoquinoline structures and mutational analysis reveal active site F482 as an underappreciated allosteric stabilizer of AIF dimerization. This conformational discovery pipeline illustrates TR-HT-SAXS as an effective technology for targeting chemical leads to important macromolecular states.
		+
		+	Chemical screening by time-resolved X-ray scattering to discover allosteric probes.,Brosey CA, Link TM, Shen R, Moiani D, Burnett K, Hura GL, Jones DE, Tainer JA Nat Chem Biol. 2024 Apr 26. doi: 10.1038/s41589-024-01609-1. PMID:38671223<ref>PMID:38671223</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 8d3i" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 11:58, 8 November 2023

2023-11-08T11:58:26Z

←Older revision		Revision as of 11:58, 8 November 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8d3i is ~~ON HOLD until Paper Publication~~	+	==Crystal structure of human Apoptosis-Inducing Factor (AIF) W196A mutant complexed with quinolin-4-amine==
-		+	<StructureSection load='8d3i' size='340' side='right'caption='[[8d3i]], [[Resolution\|resolution]] 2.65Å' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[8d3i]] 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=8D3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8D3I FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.65Å</td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1LM:QUINOLIN-4-AMINE'>1LM</scene>, <scene name='pdbligand=CSX:S-OXY+CYSTEINE'>CSX</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8d3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8d3i OCA], [https://pdbe.org/8d3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8d3i RCSB], [https://www.ebi.ac.uk/pdbsum/8d3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8d3i ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/AIFM1_HUMAN AIFM1_HUMAN] Defects in AIFM1 are the cause of combined oxidative phosphorylation deficiency type 6 (COXPD6) [MIM:[https://omim.org/entry/300816 300816]. It is a mitochondrial disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting.<ref>PMID:20362274</ref> <ref>PMID:22019070</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/AIFM1_HUMAN AIFM1_HUMAN] Probable oxidoreductase that has a dual role in controlling cellular life and death; during apoptosis, it is translocated from the mitochondria to the nucleus to function as a proapoptotic factor in a caspase-independent pathway, while in normal mitochondria, it functions as an antiapoptotic factor via its oxidoreductase activity. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Interacts with EIF3G,and thereby inhibits the EIF3 machinery and protein synthesis, and activates casapse-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Binds to DNA in a sequence-independent manner.<ref>PMID:17094969</ref> <ref>PMID:19418225</ref> <ref>PMID:20362274</ref>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Brosey CA]]
		+	[[Category: Tainer JA]]

OCA at 03:59, 10 August 2022

2022-08-10T03:59:35Z

←Older revision		Revision as of 03:59, 10 August 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8d3i is ON HOLD	+	The entry 8d3i is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8d3i" [edit=sysop:move=sysop]

2022-06-08T04:35:25Z

Protected "8d3i" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:35, 8 June 2022

OCA: New page: '''Unreleased structure''' The entry 8d3i is ON HOLD Authors: Description: Category: Unreleased Structures

2022-06-08T04:35:24Z

New page: '''Unreleased structure''' The entry 8d3i is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8d3i is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]