OCA at 08:06, 11 October 2023

OCA — Wed, 11 Oct 2023 08:06:50 GMT

←Older revision		Revision as of 08:06, 11 October 2023
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-	====	+	==Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods==
-	<StructureSection load='6v9n' size='340' side='right'caption='[[6v9n]]' scene=''>	+	<StructureSection load='6v9n' size='340' side='right'caption='[[6v9n]], [[Resolution\|resolution]] 1.65Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6v9n]] 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=6V9N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V9N 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=6v9n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v9n OCA], [~~http~~://pdbe.org/6v9n PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6v9n RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6v9n PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6v9n 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]] 1.648Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=QTD:4-phenoxybenzene-1-sulfonamide'>QTD</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=6v9n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v9n OCA], [https://pdbe.org/6v9n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v9n RCSB], [https://www.ebi.ac.uk/pdbsum/6v9n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v9n ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/RASH_HUMAN RASH_HUMAN] Defects in HRAS are the cause of faciocutaneoskeletal syndrome (FCSS) [MIM:[https://omim.org/entry/218040 218040]. A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities.<ref>PMID:16170316</ref> <ref>PMID:16329078</ref> <ref>PMID:16443854</ref> <ref>PMID:17054105</ref> <ref>PMID:18247425</ref> <ref>PMID:18039947</ref> <ref>PMID:19995790</ref> Defects in HRAS are the cause of congenital myopathy with excess of muscle spindles (CMEMS) [MIM:[https://omim.org/entry/218040 218040]. CMEMS is a variant of Costello syndrome.<ref>PMID:17412879</ref> Defects in HRAS may be a cause of susceptibility to Hurthle cell thyroid carcinoma (HCTC) [MIM:[https://omim.org/entry/607464 607464]. Hurthle cell thyroid carcinoma accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms. Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. Defects in HRAS are a cause of susceptibility to bladder cancer (BLC) [MIM:[https://omim.org/entry/109800 109800]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC).<ref>PMID:1459726</ref> Defects in HRAS are the cause of Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:[https://omim.org/entry/163200 163200]. A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis.<ref>PMID:22683711</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/RASH_HUMAN RASH_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.<ref>PMID:14500341</ref> <ref>PMID:9020151</ref> <ref>PMID:12740440</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1(cat)-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.
		+
		+	Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods.,Sarkar D, Olejniczak ET, Phan J, Coker JA, Sai J, Arnold A, Beesetty Y, Waterson AG, Fesik SW J Med Chem. 2020 Aug 13;63(15):8325-8337. doi: 10.1021/acs.jmedchem.0c00511. Epub, 2020 Aug 3. PMID:32673492<ref>PMID:32673492</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6v9n" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Son of sevenless\|Son of sevenless]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Fesik SW]]
		+	[[Category: Phan J]]

OCA at 11:16, 26 August 2020

OCA — Wed, 26 Aug 2020 11:16:09 GMT

←Older revision		Revision as of 11:16, 26 August 2020
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-	'''Unreleased structure'''

-	~~The entry~~ 6v9n ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='6v9n' size='340' side='right'caption='[[6v9n]]' scene=''>
-	~~Authors~~: ~~Phan, J~~.~~, Fesik, S~~.W.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	~~Description: Expanding~~ the ~~Chemical Landscape of SOS1 Activators Using Fragment Based Methods~~	+	</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=6v9n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v9n OCA], [http://pdbe.org/6v9n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v9n RCSB], [http://www.ebi.ac.uk/pdbsum/6v9n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v9n ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Fesik~~, S.W]]	+	__TOC__
-	[[Category: ~~Phan, J~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 06:48, 1 January 2020

OCA — Wed, 01 Jan 2020 06:48:03 GMT

←Older revision		Revision as of 06:48, 1 January 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6v9n is ON HOLD	+	The entry 6v9n is ON HOLD until Paper Publication

	Authors: Phan, J., Fesik, S.W.		Authors: Phan, J., Fesik, S.W.

OCA: Protected "6v9n" [edit=sysop:move=sysop]

OCA — Wed, 25 Dec 2019 07:32:49 GMT

Protected "6v9n" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:32, 25 December 2019

OCA: New page: '''Unreleased structure''' The entry 6v9n is ON HOLD Authors: Phan, J., Fesik, S.W. Description: Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods [[Cate...

OCA — Wed, 25 Dec 2019 07:32:47 GMT

New page: '''Unreleased structure''' The entry 6v9n is ON HOLD Authors: Phan, J., Fesik, S.W. Description: Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods [[Cate...

New page

'''Unreleased structure'''

The entry 6v9n is ON HOLD

Authors: Phan, J., Fesik, S.W.

Description: Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods
[[Category: Unreleased Structures]]
[[Category: Fesik, S.W]]
[[Category: Phan, J]]

6v9n - Revision history

OCA at 08:06, 11 October 2023

OCA at 11:16, 26 August 2020

OCA at 06:48, 1 January 2020

OCA: Protected "6v9n" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6v9n is ON HOLD Authors: Phan, J., Fesik, S.W. Description: Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods [[Cate...