5fd2 - Revision history

OCA at 12:31, 6 March 2024

2024-03-06T12:31:02Z

←Older revision		Revision as of 12:31, 6 March 2024
Line 12:		Line 12:
	== Function ==		== 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.		[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 ==
-	One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/alphaC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that alpha-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.
-
-	Purinylpyridinylamino-based DFG-in/alphaC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.,Liu L, Lee MR, Kim JL, Whittington DA, Bregman H, Hua Z, Lewis RT, Martin MW, Nishimura N, Potashman M, Yang K, Yi S, Vaida KR, Epstein LF, Babij C, Fernando M, Carnahan J, Norman MH Bioorg Med Chem. 2016 May 15;24(10):2215-34. doi: 10.1016/j.bmc.2016.03.055. Epub, 2016 Apr 13. PMID:27085672<ref>PMID:27085672</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5fd2" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 06:46, 19 July 2023

2023-07-19T06:46:41Z

←Older revision		Revision as of 06:46, 19 July 2023
Line 3:		Line 3:
	<StructureSection load='5fd2' size='340' side='right'caption='[[5fd2]], [[Resolution\|resolution]] 2.89Å' scene=''>		<StructureSection load='5fd2' size='340' side='right'caption='[[5fd2]], [[Resolution\|resolution]] 2.89Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5fd2]] 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=5FD2 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5FD2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5fd2]] 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=5FD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FD2 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=5XJ:6~~-[2-[~~[3-(DIMETHYLSULFAMOYLAMINO)-2,6-BIS(FLUORANYL)PHENYL~~]~~AMINO~~]~~PYRIDIN-3-YL]-7~{H}-PURINE'>5XJ</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]] 2.89Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>BRAF, BRAF1, RAFB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5XJ:6-[2-[[3-(DIMETHYLSULFAMOYLAMINO)-2,6-BIS(FLUORANYL)PHENYL]AMINO]PYRIDIN-3-YL]-7~{H}-PURINE'>5XJ</scene></td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Non~~-~~specific_serine/threonine_protein_kinase Non~~-~~specific serine/threonine protein kinase], with EC number~~ [~~http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=~~2.7~~.11.1 2.7.11.1]~~ </~~span~~></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=5fd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fd2 OCA], [https://pdbe.org/5fd2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fd2 RCSB], [https://www.ebi.ac.uk/pdbsum/5fd2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fd2 ProSAT]</span></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=5fd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fd2 OCA], [~~http~~://pdbe.org/5fd2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5fd2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5fd2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5fd2 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://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:[~~http~~://omim.org/entry/114500 114500]].<ref>PMID:18974108</ref> Defects in BRAF are involved in 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.<ref>PMID:18974108</ref> <ref>PMID:12460919</ref> Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:[~~http~~://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:[~~http~~://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:[~~http~~://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:[~~http~~://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>	+	[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 ==		== Function ==
-	[~~[http~~://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.	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 29:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Epstein LF]]
-	[[Category: Epstein~~, L F~~]]	+	[[Category: Whittington DA]]
-	[[Category: Whittington~~, D A]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Melanoma]]~~	+
-	~~[[Category: Phosphotransferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 07:12, 6 May 2020

2020-05-06T07:12:56Z

←Older revision		Revision as of 07:12, 6 May 2020
Line 1:		Line 1:

	==B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based inhibitor==		==B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based inhibitor==
-	<StructureSection load='5fd2' size='340' side='right' caption='[[5fd2]], [[Resolution\|resolution]] 2.89Å' scene=''>	+	<StructureSection load='5fd2' size='340' side='right'caption='[[5fd2]], [[Resolution\|resolution]] 2.89Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5fd2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FD2 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5FD2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5fd2]] 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=5FD2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FD2 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5XJ:6-[2-[[3-(DIMETHYLSULFAMOYLAMINO)-2,6-BIS(FLUORANYL)PHENYL]AMINO]PYRIDIN-3-YL]-7~{H}-PURINE'>5XJ</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5XJ:6-[2-[[3-(DIMETHYLSULFAMOYLAMINO)-2,6-BIS(FLUORANYL)PHENYL]AMINO]PYRIDIN-3-YL]-7~{H}-PURINE'>5XJ</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BRAF, BRAF1, RAFB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5fd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fd2 OCA], [http://pdbe.org/5fd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fd2 RCSB], [http://www.ebi.ac.uk/pdbsum/5fd2 PDBsum]</span></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=5fd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fd2 OCA], [http://pdbe.org/5fd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fd2 RCSB], [http://www.ebi.ac.uk/pdbsum/5fd2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fd2 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5fd2" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5fd2" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Epstein, L F]]		[[Category: Epstein, L F]]

OCA at 03:33, 11 May 2016

2016-05-11T03:33:15Z

←Older revision		Revision as of 03:33, 11 May 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The entry ~~5fd2~~ is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based inhibitor==
		+	<StructureSection load='5fd2' size='340' side='right' caption='[[5fd2]], [[Resolution\|resolution]] 2.89Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5fd2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FD2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FD2 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5XJ:6-[2-[[3-(DIMETHYLSULFAMOYLAMINO)-2,6-BIS(FLUORANYL)PHENYL]AMINO]PYRIDIN-3-YL]-7~{H}-PURINE'>5XJ</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5fd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fd2 OCA], [http://pdbe.org/5fd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fd2 RCSB], [http://www.ebi.ac.uk/pdbsum/5fd2 PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://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:[http://omim.org/entry/114500 114500]].<ref>PMID:18974108</ref> Defects in BRAF are involved in 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.<ref>PMID:18974108</ref> <ref>PMID:12460919</ref> Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:[http://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:[http://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:[http://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:[http://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 ==
		+	[[http://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 ==
		+	One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/alphaC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that alpha-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.

-	~~Authors~~: Whittington, ~~D.A.~~, Epstein, L.F.	+	Purinylpyridinylamino-based DFG-in/alphaC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.,Liu L, Lee MR, Kim JL, Whittington DA, Bregman H, Hua Z, Lewis RT, Martin MW, Nishimura N, Potashman M, Yang K, Yi S, Vaida KR, Epstein LF, Babij C, Fernando M, Carnahan J, Norman MH Bioorg Med Chem. 2016 May 15;24(10):2215-34. doi: 10.1016/j.bmc.2016.03.055. Epub, 2016 Apr 13. PMID:27085672<ref>PMID:27085672</ref>

-	~~Description: B~~-~~Raf wild~~-~~type kinase domain in complex with a purinylpyridinylamino~~-~~based inhibitor~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Whittington, D.A]]	+	<div class="pdbe-citations 5fd2" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Epstein, L.F~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Epstein, L F]]
		+	[[Category: Whittington, D A]]
		+	[[Category: Inhibitor]]
		+	[[Category: Melanoma]]
		+	[[Category: Phosphotransferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 17:47, 30 December 2015

2015-12-30T17:47:52Z

←Older revision		Revision as of 17:47, 30 December 2015
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5fd2 is ON HOLD	+	The entry 5fd2 is ON HOLD until Paper Publication

	Authors: Whittington, D.A., Epstein, L.F.		Authors: Whittington, D.A., Epstein, L.F.

OCA: Protected "5fd2" [edit=sysop:move=sysop]

2015-12-23T11:28:44Z

Protected "5fd2" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:28, 23 December 2015

OCA: New page: '''Unreleased structure''' The entry 5fd2 is ON HOLD Authors: Whittington, D.A., Epstein, L.F. Description: B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based ...

2015-12-23T11:28:43Z

New page: '''Unreleased structure''' The entry 5fd2 is ON HOLD Authors: Whittington, D.A., Epstein, L.F. Description: B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based ...

New page

'''Unreleased structure'''

The entry 5fd2 is ON HOLD

Authors: Whittington, D.A., Epstein, L.F.

Description: B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based inhibitor
[[Category: Unreleased Structures]]
[[Category: Whittington, D.A]]
[[Category: Epstein, L.F]]