View source for 3js2


==Crystal structure of minimal kinase domain of fibroblast growth factor receptor 1 in complex with 5-(2-thienyl)nicotinic acid==
<StructureSection load='3js2' size='340' side='right'caption='[[3js2]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3js2]] 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=3JS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JS2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=VM1:5-(2-THIENYL)NICOTINIC+ACID'>VM1</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=3js2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3js2 OCA], [https://pdbe.org/3js2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3js2 RCSB], [https://www.ebi.ac.uk/pdbsum/3js2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3js2 ProSAT]</span></td></tr>
</table>
== Disease ==
[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 ==
[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> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/js/3js2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3js2 ConSurf].
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== Publication Abstract from PubMed ==
Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC(50) values of 23 and 50 muM. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 muM. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.

Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.,Ravindranathan KP, Mandiyan V, Ekkati AR, Bae JH, Schlessinger J, Jorgensen WL J Med Chem. 2010 Feb 25;53(4):1662-72. PMID:20121196<ref>PMID:20121196</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3js2" style="background-color:#fffaf0;"></div>

==See Also==
*[[Fibroblast growth factor receptor 3D receptor|Fibroblast growth factor receptor 3D receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bae JH]]
[[Category: Ekkati AR]]
[[Category: Jorgensen WL]]
[[Category: Mandiyan V]]
[[Category: Ravindranathan KP]]
[[Category: Schlessinger J]]