6gge - Revision history

OCA at 09:29, 30 October 2019

OCA — Wed, 30 Oct 2019 09:29:39 GMT

←Older revision		Revision as of 09:29, 30 October 2019
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	<StructureSection load='6gge' size='340' side='right'caption='[[6gge]], [[Resolution\|resolution]] 1.25Å' scene=''>		<StructureSection load='6gge' size='340' side='right'caption='[[6gge]], [[Resolution\|resolution]] 1.25Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6gge]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGE FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6gge]] is a 2 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=6GGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EYE:[9-ethyl-7-(5-methylthiophen-2-yl)carbazol-3-yl]methyl-methyl-azanium'>EYE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EYE:[9-ethyl-7-(5-methylthiophen-2-yl)carbazol-3-yl]methyl-methyl-azanium'>EYE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TP53, P53 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6gge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gge OCA], [http://pdbe.org/6gge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gge RCSB], [http://www.ebi.ac.uk/pdbsum/6gge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gge 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=6gge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gge OCA], [http://pdbe.org/6gge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gge RCSB], [http://www.ebi.ac.uk/pdbsum/6gge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gge ProSAT]</span></td></tr>
	</table>		</table>
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	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	The ~~DNA-binding domain of the tumor suppressor~~ p53 ~~is inactivated by~~ mutation ~~in approximately 50% of human cancers~~. We ~~have solved high~~-~~resolution crystal structures~~ of ~~several oncogenic mutants to investigate~~ the ~~structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants~~. ~~We found a variety of structural consequences upon mutation~~: ~~(i)~~ the ~~removal~~ of an ~~essential contact with DNA, (ii) creation~~ of ~~large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but~~ with a ~~large loss of thermodynamic stability, (iii) distortion of the DNA~~-~~binding surface, and (iv) alterations~~ to ~~surfaces not directly involved in DNA binding but involved in domain~~-~~domain interactions on binding as a tetramer. These findings explain differences in functional properties~~ and ~~associated phenotypes (e.g~~., ~~temperature sensitivity). Some mutants have~~ the ~~potential of being rescued by a generic stabilizing drug. In addition~~, a mutation-~~induced crevice~~ is ~~a potential target site~~ for a mutant-~~selective stabilizing drug~~.	+	Aim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083. Materials & methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.

-	~~Structural basis~~ for ~~understanding oncogenic~~ p53 ~~mutations and designing rescue drugs~~.,~~Joerger AC~~, ~~Ang HC~~, Fersht AR ~~Proc Natl Acad Sci U S A~~. ~~2006~~ Oct 10;~~103~~(41):~~15056~~-61. ~~Epub 2006 Oct 2~~. PMID:~~17015838~~<ref>PMID:~~17015838~~</ref>	+	A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C.,Bauer MR, Jones RN, Tareque RK, Springett B, Dingler FA, Verduci L, Patel KJ, Fersht AR, Joerger AC, Spencer J Future Med Chem. 2019 Oct;11(19):2491-2504. doi: 10.4155/fmc-2019-0181. PMID:31633398<ref>PMID:31633398</ref>

	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Bauer, M R]]		[[Category: Bauer, M R]]

OCA at 06:46, 23 May 2019

OCA — Thu, 23 May 2019 06:46:10 GMT

←Older revision		Revision as of 06:46, 23 May 2019
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-	'''Unreleased structure'''

-	The entry ~~6gge~~ is ~~ON HOLD~~	+	==p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9327==
		+	<StructureSection load='6gge' size='340' side='right'caption='[[6gge]], [[Resolution\|resolution]] 1.25Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6gge]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGE FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EYE:[9-ethyl-7-(5-methylthiophen-2-yl)carbazol-3-yl]methyl-methyl-azanium'>EYE</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6gge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gge OCA], [http://pdbe.org/6gge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gge RCSB], [http://www.ebi.ac.uk/pdbsum/6gge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gge ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:[http://omim.org/entry/133239 133239]]. Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:[http://omim.org/entry/151623 151623]]. LFS is an autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.<ref>PMID:10570149</ref> <ref>PMID:1933902</ref> <ref>PMID:1978757</ref> <ref>PMID:2259385</ref> <ref>PMID:1737852</ref> <ref>PMID:1565144</ref> <ref>PMID:7887414</ref> <ref>PMID:8825920</ref> <ref>PMID:9452042</ref> <ref>PMID:10484981</ref> Defects in TP53 are involved in head and neck squamous cell carcinomas (HNSCC) [MIM:[http://omim.org/entry/275355 275355]]; also known as squamous cell carcinoma of the head and neck. Defects in TP53 are a cause of lung cancer (LNCR) [MIM:[http://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Defects in TP53 are a cause of choroid plexus papilloma (CPLPA) [MIM:[http://omim.org/entry/260500 260500]]. Choroid plexus papilloma is a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of cerebrospinal fluid. If it undergoes malignant transformation it is called a choroid plexus carcinoma. Primary choroid plexus tumors are rare and usually occur in early childhood.<ref>PMID:12085209</ref> Defects in TP53 are a cause of adrenocortical carcinoma (ADCC) [MIM:[http://omim.org/entry/202300 202300]]. ADCC is a rare childhood tumor of the adrenal cortex. It occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome and is a component tumor in Li-Fraumeni syndrome.<ref>PMID:11481490</ref> Defects in TP53 are the cause of susceptibility to basal cell carcinoma 7 (BCC7) [MIM:[http://omim.org/entry/614740 614740]]. A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter.<ref>PMID:21946351</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; te function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis.<ref>PMID:9840937</ref> <ref>PMID:11025664</ref> <ref>PMID:12810724</ref> <ref>PMID:15186775</ref> <ref>PMID:15340061</ref> <ref>PMID:17317671</ref> <ref>PMID:17349958</ref> <ref>PMID:19556538</ref> <ref>PMID:20673990</ref> <ref>PMID:20959462</ref> <ref>PMID:22726440</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.

-	~~Authors~~:	+	Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.,Joerger AC, Ang HC, Fersht AR Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15056-61. Epub 2006 Oct 2. PMID:17015838<ref>PMID:17015838</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6gge" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Bauer, M R]]
		+	[[Category: Joerger, A C]]
		+	[[Category: Cancer therapy]]
		+	[[Category: Dna binding protein]]
		+	[[Category: Molecular chaperone]]
		+	[[Category: Oncogenic mutant]]
		+	[[Category: P53]]
		+	[[Category: Protein misfolding]]
		+	[[Category: Small-molecule stabilizer]]
		+	[[Category: Transcription factor]]
		+	[[Category: Tumor supressor]]

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

OCA — Wed, 09 May 2018 05:08:05 GMT

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

←Older revision

Revision as of 05:08, 9 May 2018

OCA: New page: '''Unreleased structure''' The entry 6gge is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 09 May 2018 05:08:04 GMT

New page: '''Unreleased structure''' The entry 6gge is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6gge is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]