1p9j
From Proteopedia
Solution structure and dynamics of the EGF/TGF-alpha chimera T1E
Structural highlights
DiseaseEGF_HUMAN Defects in EGF are the cause of hypomagnesemia type 4 (HOMG4) [MIM:611718; also known as renal hypomagnesemia normocalciuric. HOMG4 is a disorder characterized by massive renal hypomagnesemia and normal levels of serum calcium and calcium excretion. Clinical features include seizures, mild-to mederate psychomotor retardation, and brisk tendon reflexes.[1] FunctionEGF_HUMAN EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in the renal distal convoluted tubule via engagement of EGFR and activation of the magnesium channel TRPM6.[2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedVarious chimeras of the ErbB1-specific ligands epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) display an enlarged repertoire as activators of ErbB2.ErbB3 heterodimers. Mutational analysis indicated that particularly residues in the N terminus and B-loop region of these ligands are involved in the broadened receptor specificity. In order to understand the receptor specificity of T1E, a chimeric ligand constructed by the introduction of the linear N-terminal region of TGFalpha into EGF, we determined in this study the solution structure and dynamics of T1E by multidimensional NMR analysis. Subsequently, we studied the structural characteristics of T1E binding to both ErbB1 and ErbB3 by superposition modeling of its structure on the known crystal structures of ErbB3 and liganded ErbB1 complexes. The results show that the overall structure of T1E in solution is very similar to that of native EGF and TGFalpha but that its N terminus shows an extended structure that is appropriately positioned to form a triple beta-sheet with the large antiparallel beta-sheet in the B-loop region. This conformational effect of the N terminus together with the large overall flexibility of T1E, as determined by 15N NMR relaxation analysis, may be a facilitative property for its broad receptor specificity. The structural superposition models indicate that hydrophobic and electrostatic interactions of the N terminus and B-loop of T1E are particularly important for its binding to ErbB3. Structural analysis of an epidermal growth factor/transforming growth factor-alpha chimera with unique ErbB binding specificity.,Wingens M, Walma T, van Ingen H, Stortelers C, van Leeuwen JE, van Zoelen EJ, Vuister GW J Biol Chem. 2003 Oct 3;278(40):39114-23. Epub 2003 Jul 16. PMID:12869572[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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