5eg3 | pdb_00005eg3

Crystal Structure of the Activated FGF Receptor 2 (FGFR2) Kinase Domain in complex with the cSH2 domain of Phospholipase C gamma (PLCgamma)

spinqualitylabelsall models 5eg3, resolution 2.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5eg3 is a 2 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.606Å Ligands: ACP, MG, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease FGFR2_HUMAN Defects in FGFR2 are the cause of Crouzon syndrome (CS) [MIM:123500; also called craniofacial dysostosis type I (CFD1). CS is an autosomal dominant syndrome characterized by craniosynostosis (premature fusion of the skull sutures), hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism. [:] Defects in FGFR2 are a cause of Jackson-Weiss syndrome (JWS) [MIM:123150. JWS is an autosomal dominant craniosynostosis syndrome characterized by craniofacial abnormalities and abnormality of the feet: broad great toes with medial deviation and tarsal-metatarsal coalescence. Defects in FGFR2 are a cause of Apert syndrome (APRS) [MIM:101200; also known as acrocephalosyndactyly type 1 (ACS1). APRS is a syndrome characterized by facio-cranio-synostosis, osseous and membranous syndactyly of the four extremities, and midface hypoplasia. The craniosynostosis is bicoronal and results in acrocephaly of brachysphenocephalic type. Syndactyly of the fingers and toes may be total (mitten hands and sock feet) or partial affecting the second, third, and fourth digits. Intellectual deficit is frequent and often severe, usually being associated with cerebral malformations. Defects in FGFR2 are a cause of Pfeiffer syndrome (PS) [MIM: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. Three subtypes of Pfeiffer syndrome have been described: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). Defects in FGFR2 are the cause of Beare-Stevenson cutis gyrata syndrome (BSCGS) [MIM:123790. BSCGS is an autosomal dominant condition is characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Defects in FGFR2 are the cause of familial scaphocephaly syndrome (FSPC) [MIM:609579; also known as scaphocephaly with maxillary retrusion and mental retardation. FSPC is an autosomal dominant craniosynostosis syndrome characterized by scaphocephaly, macrocephaly, hypertelorism, maxillary retrusion, and mild intellectual disability. Scaphocephaly is the most common of the craniosynostosis conditions and is characterized by a long, narrow head. It is due to premature fusion of the sagittal suture or from external deformation. Defects in FGFR2 are a cause of lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730; also known as Levy-Hollister syndrome. LADDS is a form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. LADDS is an autosomal dominant syndrome characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. Defects in FGFR2 are the cause of Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis (ABS2) [MIM:207410. A rare syndrome characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures. Arachnodactyly and/or camptodactyly have also been reported. Defects in FGFR2 are the cause of Bent bone dysplasia syndrome (BBDS) [MIM:614592. BBDS is a perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Dysmorphic facial features included low-set ears, hypertelorism, midface hypoplasia, prematurely erupted fetal teeth, and micrognathia. Function FGFR2_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. 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. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. Publication Abstract from PubMed The molecular basis by which receptor tyrosine kinases (RTKs) recruit and phosphorylate Src Homology 2 (SH2) domain-containing substrates has remained elusive. We used X-ray crystallography, NMR spectroscopy, and cell-based assays to demonstrate that recruitment and phosphorylation of Phospholipase Cgamma (PLCgamma), a prototypical SH2 containing substrate, by FGF receptors (FGFR) entails formation of an allosteric 2:1 FGFR-PLCgamma complex. We show that the engagement of pTyr-binding pocket of the cSH2 domain of PLCgamma by the phosphorylated tail of an FGFR kinase induces a conformational change at the region past the cSH2 core domain encompassing Tyr-771 and Tyr-783 to facilitate the binding/phosphorylation of these tyrosines by another FGFR kinase in trans. Our data overturn the current paradigm that recruitment and phosphorylation of substrates are carried out by the same RTK monomer in cis and disclose an obligatory role for receptor dimerization in substrate phosphorylation in addition to its canonical role in kinase activation. Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cgamma.,Huang Z, Marsiglia WM, Basu Roy U, Rahimi N, Ilghari D, Wang H, Chen H, Gai W, Blais S, Neubert TA, Mansukhani A, Traaseth NJ, Li X, Mohammadi M Mol Cell. 2016 Jan 7;61(1):98-110. doi: 10.1016/j.molcel.2015.11.010. Epub 2015, Dec 10. PMID:26687682 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fibroblast growth factor receptor 3D receptor

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