OCA at 15:15, 18 October 2023

OCA — Wed, 18 Oct 2023 15:15:44 GMT

←Older revision		Revision as of 15:15, 18 October 2023
Line 1:		Line 1:

	==Crystal structure of bRaf in complex with inhibitor GNE-0749==		==Crystal structure of bRaf in complex with inhibitor GNE-0749==
-	<StructureSection load='7k0v' size='340' side='right'caption='[[7k0v]]' scene=''>	+	<StructureSection load='7k0v' size='340' side='right'caption='[[7k0v]], [[Resolution\|resolution]] 1.93Å' 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=7K0V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K0V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7k0v]] is a 4 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=7K0V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K0V FirstGlance]. <br>
-	</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=7k0v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k0v OCA], [https://pdbe.org/7k0v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k0v RCSB], [https://www.ebi.ac.uk/pdbsum/7k0v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k0v 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]] 1.93Å</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=VQP:N-(3,3-dimethylbutyl)-N-{2-fluoro-5-[(5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]-4-methylphenyl}urea'>VQP</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=7k0v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k0v OCA], [https://pdbe.org/7k0v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k0v RCSB], [https://www.ebi.ac.uk/pdbsum/7k0v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k0v ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN] Note=Defects in BRAF are found in a wide range of cancers.<ref>PMID:18974108</ref> Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].<ref>PMID:18974108</ref> Defects in BRAF are involved in lung cancer (LNCR) [MIM:[https://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.<ref>PMID:18974108</ref> <ref>PMID:12460919</ref> Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:[https://omim.org/entry/605027 605027]. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.<ref>PMID:18974108</ref> <ref>PMID:14612909</ref> Defects in BRAF are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[https://omim.org/entry/115150 115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.<ref>PMID:18974108</ref> Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM:[https://omim.org/entry/613706 613706]. Noonan syndrome is a disorder characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.<ref>PMID:18974108</ref> <ref>PMID:19206169</ref> Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:[https://omim.org/entry/613707 613707]. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.<ref>PMID:18974108</ref> <ref>PMID:19206169</ref> Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.<ref>PMID:18974108</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN] Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.
		+
		+	Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.,Huestis MP, Dela Cruz D, DiPasquale AG, Durk MR, Eigenbrot C, Gibbons P, Gobbi A, Hunsaker TL, La H, Leung DH, Liu W, Malek S, Merchant M, Moffat JG, Muli CS, Orr CJ, Parr BT, Shanahan F, Sneeringer CJ, Wang W, Yen I, Yin J, Siu M, Rudolph J J Med Chem. 2021 Apr 8;64(7):3940-3955. doi: 10.1021/acs.jmedchem.0c02085. Epub, 2021 Mar 29. PMID:33780623<ref>PMID:33780623</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7k0v" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Eigenbrot CE]]		[[Category: Eigenbrot CE]]
	[[Category: Wang W]]		[[Category: Wang W]]
	[[Category: Yin J]]		[[Category: Yin J]]

OCA at 09:19, 26 May 2021

OCA — Wed, 26 May 2021 09:19:54 GMT

←Older revision		Revision as of 09:19, 26 May 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7k0v is ~~ON HOLD until Paper Publication~~	+	==Crystal structure of bRaf in complex with inhibitor GNE-0749==
-		+	<StructureSection load='7k0v' size='340' side='right'caption='[[7k0v]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K0V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K0V FirstGlance]. <br>
-	~~Description~~:	+	</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=7k0v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k0v OCA], [https://pdbe.org/7k0v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k0v RCSB], [https://www.ebi.ac.uk/pdbsum/7k0v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k0v ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Eigenbrot CE]]
		+	[[Category: Wang W]]
		+	[[Category: Yin J]]

OCA at 04:16, 14 October 2020

OCA — Wed, 14 Oct 2020 04:16:23 GMT

←Older revision		Revision as of 04:16, 14 October 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7k0v is ON HOLD	+	The entry 7k0v is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7k0v" [edit=sysop:move=sysop]

OCA — Wed, 16 Sep 2020 07:04:52 GMT

Protected "7k0v" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:04, 16 September 2020

OCA: New page: '''Unreleased structure''' The entry 7k0v is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 16 Sep 2020 07:04:49 GMT

New page: '''Unreleased structure''' The entry 7k0v is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7k0v is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

7k0v - Revision history

OCA at 15:15, 18 October 2023

OCA at 09:19, 26 May 2021

OCA at 04:16, 14 October 2020

OCA: Protected "7k0v" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7k0v is ON HOLD Authors: Description: Category: Unreleased Structures