1iil

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spinqualitylabelsall models 1iil, resolution 2.3Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF PRO253ARG APERT MUTANT FGF RECEPTOR 2 (FGFR2) IN COMPLEX WITH FGF2

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Apert syndrome (AS) is characterized by craniosynostosis (premature fusion, of cranial sutures) and severe syndactyly of the hands and feet. Two, activating mutations, Ser-252 --> Trp and Pro-253 --> Arg, in fibroblast, growth factor receptor 2 (FGFR2) account for nearly all known cases of AS., To elucidate the mechanism by which these substitutions cause AS, we, determined the crystal structures of these two FGFR2 mutants in complex, with fibroblast growth factor 2 (FGF2). These structures demonstrate that, both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these, structures and sequence alignment of the FGF family, we propose that the, Pro-253 --> Arg mutation will indiscriminately increase the affinity of, FGFR2 toward any FGF. In contrast, the Ser-252 --> Trp mutation will, selectively enhance the affinity of FGFR2 toward a limited subset of FGFs., These predictions are consistent with previous biochemical data describing, the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand, affinity and specificity may allow inappropriate autocrine or paracrine, activation of FGFR2. Furthermore, the distinct gain-of-function, interactions observed in each crystal structure provide a model to explain, the phenotypic variability among AS patients.

Disease

Known diseases associated with this structure: Hypophosphatemic rickets, autosomal dominant OMIM:[605380], Osteomalacia, tumor-induced OMIM:[605380], Tumoral calcinosis, hyperphosphatemic, familial OMIM:[605380]

About this Structure

1IIL is a Protein complex structure of sequences from Homo sapiens. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

Reference

Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome., Ibrahimi OA, Eliseenkova AV, Plotnikov AN, Yu K, Ornitz DM, Mohammadi M, Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7182-7. Epub 2001 Jun 5. PMID:11390973

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