4rwi - Revision history

OCA at 17:57, 20 September 2023

OCA — Wed, 20 Sep 2023 17:57:47 GMT

←Older revision		Revision as of 17:57, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4rwi]] 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=4RWI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RWI FirstGlance]. <br>		<table><tr><td colspan='2'>[[4rwi]] 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=4RWI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RWI 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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [https://pdbe.org/4rwi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [https://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi 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]] 2.292Å</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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [https://pdbe.org/4rwi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [https://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==

OCA at 08:31, 8 March 2023

OCA — Wed, 08 Mar 2023 08:31:40 GMT

←Older revision		Revision as of 08:31, 8 March 2023
Line 1:		Line 1:

	==Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo==		==Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo==
-	<StructureSection load='4rwi' size='340' side='right' caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>	+	<StructureSection load='4rwi' size='340' side='right'caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4rwi]] 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=4RWI OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4RWI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4rwi]] 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=4RWI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RWI FirstGlance]. <br>
-	</td></tr>~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rwj\|4rwj]], [[4rwk\|4rwk]], [[4rwl\|4rwl]]</td></tr>~~	+	</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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [https://pdbe.org/4rwi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [https://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BFGFR, CEK, FGFBR, FGFR1, FLG, FLT2, HBGFR ([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/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [~~http~~://pdbe.org/4rwi PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN]] Defects in FGFR1 are a cause of Pfeiffer syndrome (PS) [MIM:[~~http~~://omim.org/entry/101600 101600]]; also known as acrocephalosyndactyly type V (ACS5). PS is characterized by craniosynostosis (premature fusion of the skull sutures) with deviation and enlargement of the thumbs and great toes, brachymesophalangy, with phalangeal ankylosis and a varying degree of soft tissue syndactyly.<ref>PMID:20139426</ref> <ref>PMID:7874169</ref> Defects in FGFR1 are the cause of hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:[~~http~~://omim.org/entry/147950 147950]]. A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).<ref>PMID:20139426</ref> <ref>PMID:12627230</ref> <ref>PMID:15001591</ref> <ref>PMID:15605412</ref> <ref>PMID:15845591</ref> <ref>PMID:16882753</ref> <ref>PMID:16764984</ref> <ref>PMID:16757108</ref> <ref>PMID:16606836</ref> <ref>PMID:17154279</ref> Defects in FGFR1 are the cause of osteoglophonic dysplasia (OGD) [MIM:[~~http~~://omim.org/entry/166250 166250]]; also known as osteoglophonic dwarfism. OGD is characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant.<ref>PMID:20139426</ref> <ref>PMID:15625620</ref> <ref>PMID:16470795</ref> Defects in FGFR1 are the cause of trigonocephaly type 1 (TRIGNO1) [MIM:[~~http~~://omim.org/entry/190440 190440]]. A keel-shaped deformation of the forehead resulting from premature fusion of the frontal suture. Trigonocephaly may occur also as a part of a syndrome.<ref>PMID:20139426</ref> <ref>PMID:11173846</ref> Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow.<ref>PMID:20139426</ref> Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CEP110. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CEP110-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.	+	[https://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN] Defects in FGFR1 are a cause of Pfeiffer syndrome (PS) [MIM:[https://omim.org/entry/101600 101600]; also known as acrocephalosyndactyly type V (ACS5). PS is characterized by craniosynostosis (premature fusion of the skull sutures) with deviation and enlargement of the thumbs and great toes, brachymesophalangy, with phalangeal ankylosis and a varying degree of soft tissue syndactyly.<ref>PMID:20139426</ref> <ref>PMID:7874169</ref> Defects in FGFR1 are the cause of hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:[https://omim.org/entry/147950 147950]. A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).<ref>PMID:20139426</ref> <ref>PMID:12627230</ref> <ref>PMID:15001591</ref> <ref>PMID:15605412</ref> <ref>PMID:15845591</ref> <ref>PMID:16882753</ref> <ref>PMID:16764984</ref> <ref>PMID:16757108</ref> <ref>PMID:16606836</ref> <ref>PMID:17154279</ref> Defects in FGFR1 are the cause of osteoglophonic dysplasia (OGD) [MIM:[https://omim.org/entry/166250 166250]; also known as osteoglophonic dwarfism. OGD is characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant.<ref>PMID:20139426</ref> <ref>PMID:15625620</ref> <ref>PMID:16470795</ref> Defects in FGFR1 are the cause of trigonocephaly type 1 (TRIGNO1) [MIM:[https://omim.org/entry/190440 190440]. A keel-shaped deformation of the forehead resulting from premature fusion of the frontal suture. Trigonocephaly may occur also as a part of a syndrome.<ref>PMID:20139426</ref> <ref>PMID:11173846</ref> Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow.<ref>PMID:20139426</ref> Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CEP110. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CEP110-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.<ref>PMID:20139426</ref> <ref>PMID:1379697</ref> <ref>PMID:1379698</ref> <ref>PMID:8622701</ref> <ref>PMID:8663044</ref> <ref>PMID:11353842</ref> <ref>PMID:12181353</ref> <ref>PMID:15117958</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:19261810</ref> <ref>PMID:19224897</ref> <ref>PMID:21765395</ref> <ref>PMID:10830168</ref> <ref>PMID:19665973</ref> <ref>PMID:20133753</ref>	+	[https://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.<ref>PMID:20139426</ref> <ref>PMID:1379697</ref> <ref>PMID:1379698</ref> <ref>PMID:8622701</ref> <ref>PMID:8663044</ref> <ref>PMID:11353842</ref> <ref>PMID:12181353</ref> <ref>PMID:15117958</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:19261810</ref> <ref>PMID:19224897</ref> <ref>PMID:21765395</ref> <ref>PMID:10830168</ref> <ref>PMID:19665973</ref> <ref>PMID:20133753</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 4rwi" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4rwi" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Fibroblast growth factor receptor 3D receptor\|Fibroblast growth factor receptor 3D receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Receptor protein-tyrosine kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Anderson~~, K S~~]]	+	[[Category: Anderson KS]]
-	[[Category: Sohl~~, C D]]~~	+	[[Category: Sohl CD]]
-	~~[[Category: Gatekeeper mutation]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Proto-oncogene]]~~	+
-	~~[[Category: Receptor tyrosine kinase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 09:11, 22 November 2017

OCA — Wed, 22 Nov 2017 09:11:18 GMT

←Older revision		Revision as of 09:11, 22 November 2017
Line 3:		Line 3:
	<StructureSection load='4rwi' size='340' side='right' caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>		<StructureSection load='4rwi' size='340' side='right' caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4rwi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RWI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RWI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4rwi]] 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=4RWI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RWI FirstGlance]. <br>
	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rwj\|4rwj]], [[4rwk\|4rwk]], [[4rwl\|4rwl]]</td></tr>		</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rwj\|4rwj]], [[4rwk\|4rwk]], [[4rwl\|4rwl]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BFGFR, CEK, FGFBR, FGFR1, FLG, FLT2, HBGFR ([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/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [http://pdbe.org/4rwi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [http://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi 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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [http://pdbe.org/4rwi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [http://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi ProSAT]</span></td></tr>
Line 25:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Anderson, K S]]		[[Category: Anderson, K S]]

OCA at 01:59, 10 March 2017

OCA — Fri, 10 Mar 2017 01:59:23 GMT

←Older revision		Revision as of 01:59, 10 March 2017
Line 1:		Line 1:
		+
	==Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo==		==Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo==
	<StructureSection load='4rwi' size='340' side='right' caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>		<StructureSection load='4rwi' size='340' side='right' caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rwj\|4rwj]], [[4rwk\|4rwk]], [[4rwl\|4rwl]]</td></tr>		</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rwj\|4rwj]], [[4rwk\|4rwk]], [[4rwl\|4rwl]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [http://www.ebi.ac.uk/pdbsum/4rwi PDBsum]</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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [http://pdbe.org/4rwi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [http://www.ebi.ac.uk/pdbsum/4rwi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rwi ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	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>
	</div>		</div>
		+	<div class="pdbe-citations 4rwi" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:51, 15 April 2015

OCA — Wed, 15 Apr 2015 12:51:18 GMT

←Older revision		Revision as of 12:51, 15 April 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo==
		+	<StructureSection load='4rwi' size='340' side='right' caption='[[4rwi]], [[Resolution\|resolution]] 2.29Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4rwi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RWI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RWI FirstGlance]. <br>
		+	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rwj\|4rwj]], [[4rwk\|4rwk]], [[4rwl\|4rwl]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4rwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rwi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rwi RCSB], [http://www.ebi.ac.uk/pdbsum/4rwi PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN]] Defects in FGFR1 are a cause of Pfeiffer syndrome (PS) [MIM:[http://omim.org/entry/101600 101600]]; also known as acrocephalosyndactyly type V (ACS5). PS is characterized by craniosynostosis (premature fusion of the skull sutures) with deviation and enlargement of the thumbs and great toes, brachymesophalangy, with phalangeal ankylosis and a varying degree of soft tissue syndactyly.<ref>PMID:20139426</ref> <ref>PMID:7874169</ref> Defects in FGFR1 are the cause of hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:[http://omim.org/entry/147950 147950]]. A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).<ref>PMID:20139426</ref> <ref>PMID:12627230</ref> <ref>PMID:15001591</ref> <ref>PMID:15605412</ref> <ref>PMID:15845591</ref> <ref>PMID:16882753</ref> <ref>PMID:16764984</ref> <ref>PMID:16757108</ref> <ref>PMID:16606836</ref> <ref>PMID:17154279</ref> Defects in FGFR1 are the cause of osteoglophonic dysplasia (OGD) [MIM:[http://omim.org/entry/166250 166250]]; also known as osteoglophonic dwarfism. OGD is characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant.<ref>PMID:20139426</ref> <ref>PMID:15625620</ref> <ref>PMID:16470795</ref> Defects in FGFR1 are the cause of trigonocephaly type 1 (TRIGNO1) [MIM:[http://omim.org/entry/190440 190440]]. A keel-shaped deformation of the forehead resulting from premature fusion of the frontal suture. Trigonocephaly may occur also as a part of a syndrome.<ref>PMID:20139426</ref> <ref>PMID:11173846</ref> Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow.<ref>PMID:20139426</ref> Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CEP110. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CEP110-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.<ref>PMID:20139426</ref> <ref>PMID:1379697</ref> <ref>PMID:1379698</ref> <ref>PMID:8622701</ref> <ref>PMID:8663044</ref> <ref>PMID:11353842</ref> <ref>PMID:12181353</ref> <ref>PMID:15117958</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:19261810</ref> <ref>PMID:19224897</ref> <ref>PMID:21765395</ref> <ref>PMID:10830168</ref> <ref>PMID:19665973</ref> <ref>PMID:20133753</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Human fibroblast growth factor receptors (FGFRs) 1-4 are a family of receptor tyrosine kinases that can serve as drivers of tumorigenesis. In particular, FGFR1 gene amplification has been implicated in squamous cell lung and breast cancers. Tyrosine kinase inhibitors (TKIs) targeting FGFR1, including AZD4547 and E3810 (Lucitanib), are currently in early phase clinical trials. Unfortunately, drug resistance limits the long-term success of TKIs, with mutations at the "gatekeeper" residue leading to tumor progression. Here we show the first structural and kinetic characterization of the FGFR1 gatekeeper mutation, V561M FGFR1. The V561M mutation confers a 38-fold increase in autophosphorylation achieved at least in part by a network of interacting residues forming a hydrophobic spine to stabilize the active conformation. Moreover, kinetic assays established that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. Structural analyses of these TKIs with wild type (WT) and gatekeeper mutant forms of FGFR1 offer clues to developing inhibitors that maintain potency against gatekeeper mutations. We show that AZD4547 affinity is preserved by V561M FGFR1 due to a flexible linker that allows multiple inhibitor binding modes. This is the first example of a TKI binding in distinct conformations to WT and gatekeeper mutant forms of FGFR, highlighting adaptable regions in both the inhibitor and binding pocket crucial for drug design. Exploiting inhibitor flexibility to overcome drug resistance has been a successful strategy for combatting diseases such as AIDS and may be an important approach for designing inhibitors effective against kinase gatekeeper mutations.

-	The ~~entry 4rwi is ON HOLD until Paper Publication~~	+	Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.,Sohl CD, Ryan MR, Luo B, Frey KM, Anderson KS ACS Chem Biol. 2015 Feb 24. PMID:25686244<ref>PMID:25686244</ref>

-	~~Authors: Sohl~~, ~~C.D., Anderson, K~~.S.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo~~	+	== References ==
-	[[Category: ~~Unreleased Structures~~]]	+	<references/>
-	[[Category: Sohl, C.D]]	+	__TOC__
-	[[Category: ~~Anderson, K.S~~]]	+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Anderson, K S]]
		+	[[Category: Sohl, C D]]
		+	[[Category: Gatekeeper mutation]]
		+	[[Category: Kinase]]
		+	[[Category: Proto-oncogene]]
		+	[[Category: Receptor tyrosine kinase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 12:12, 31 December 2014

OCA — Wed, 31 Dec 2014 12:12:20 GMT

←Older revision		Revision as of 12:12, 31 December 2014
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4rwi is ON HOLD	+	The entry 4rwi is ON HOLD until Paper Publication

	Authors: Sohl, C.D., Anderson, K.S.		Authors: Sohl, C.D., Anderson, K.S.

OCA at 17:32, 24 December 2014

OCA — Wed, 24 Dec 2014 17:32:10 GMT

←Older revision		Revision as of 17:32, 24 December 2014
Line 6:		Line 6:

	Description: Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo		Description: Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo
		+	[[Category: Unreleased Structures]]
		+	[[Category: Sohl, C.D]]
		+	[[Category: Anderson, K.S]]

OCA: Protected "4rwi" [edit=sysop:move=sysop]

OCA — Wed, 10 Dec 2014 13:34:29 GMT

Protected "4rwi" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:34, 10 December 2014

OCA: New page: '''Unreleased structure''' The entry 4rwi is ON HOLD Authors: Sohl, C.D., Anderson, K.S. Description: Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo

OCA — Wed, 10 Dec 2014 13:34:28 GMT

New page: '''Unreleased structure''' The entry 4rwi is ON HOLD Authors: Sohl, C.D., Anderson, K.S. Description: Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo

New page

'''Unreleased structure'''

The entry 4rwi is ON HOLD

Authors: Sohl, C.D., Anderson, K.S.

Description: Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M), apo