This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
1ry7
From Proteopedia
OCA (Talk | contribs)
(New page: 200px<br /> <applet load="1ry7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ry7, resolution 3.20Å" /> '''Crystal Structure o...)
Next diff →
Revision as of 17:01, 12 November 2007
|
Crystal Structure of the 3 Ig form of FGFR3c in complex with FGF1
Contents |
Overview
The prototypical fibroblast growth factor receptor (FGFR) extracellular, domain consists of three Ig domains (D1-D3) of which the two, membrane-proximal D2 and D3 domains and the interconnecting D2-D3 linker, bear the determinants of ligand binding and specificity. In contrast, D1, and the D1-D2 linker are thought to play autoinhibitory roles in FGFR, regulation. Here, we report the crystal structure of the three-Ig form of, FGFR3c in complex with FGF1, an FGF that binds promiscuously to each of, the seven principal FGFRs. In this structure, D1 and the D1-D2 linker are, completely disordered, demonstrating that these regions are dispensable, for FGF binding. Real-time binding experiments using surface plasmon, resonance show that relative to two-Ig form, the three-Ig form of FGFR3c, exhibits lower affinity for both FGF1 and heparin. Importantly, we, demonstrate that this autoinhibition is mediated by intramolecular, interactions of D1 and the D1-D2 linker with the minimal FGF and, heparin-binding D2-D3 region. As in the FGF1-FGFR2c structure, but not the, FGF1-FGFR1c structure, the alternatively spliced betaC'-betaE loop is, ordered and interacts with FGF1 in the FGF1-FGFR3c structure. However, in, contrast to the FGF1-FGFR2c structure in which the betaC'-betaE loop, interacts with the beta-trefoil core region of FGF1, in the FGF1-FGFR3c, structure, this loop interacts extensively with the N-terminal region of, FGF1, underscoring the importance of the FGF1 N terminus in conferring, receptor-binding affinity and promiscuity. Importantly, comparison of the, three FGF1-FGFR structures shows that the flexibility of the betaC'-betaE, loop is a major determinant of ligand-binding specificity and promiscuity.
Disease
Known diseases associated with this structure: Achondroplasia OMIM:[134934], Aplasia of lacrimal and salivary glands OMIM:[602115], Bladder cancer OMIM:[134934], CATSHL syndrome OMIM:[134934], Cervical cancer, somatic OMIM:[134934], Colorectal cancer, somatic OMIM:[134934], Crouzon syndrome with acanthosis nigricans OMIM:[134934], Hypochondroplasia OMIM:[134934], LADD syndrome OMIM:[134934], LADD syndrome OMIM:[602115], Muenke syndrome OMIM:[134934], Nevus, keratinocytic, nonepidermolytic OMIM:[134934], Thanatophoric dysplasia, types I and II OMIM:[134934]
About this Structure
1RY7 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity., Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M, Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):935-40. Epub 2004 Jan 19. PMID:14732692
Page seeded by OCA on Mon Nov 12 19:08:18 2007
