2gyp

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spinqualitylabelsall models 2gyp, resolution 1.4Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Diabetes mellitus due to a frustrated Schellman motif in HNF-1a

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Maturity-onset diabetes of the young (MODY3), a monogenic form of type II, diabetes mellitus, results most commonly from mutations in hepatocyte, nuclear factor 1alpha (HNF-1alpha). Diabetes-associated mutation G20R, perturbs the dimerization domain of HNF-1alpha, an intertwined four-helix, bundle. In the wild-type structure G20 participates in a Schellman motif, to cap an alpha-helix; its dihedral angles lie in the right side of the, Ramachandran plot (alpha(L) region; phi 97 degrees). Substitutions G20R, and G20A lead to dimeric molten globules of low stability, suggesting that, the impaired function of the diabetes-associated transcription factor is, due in large part to a main-chain perturbation rather than to specific, features of the Arg side-chain. This hypothesis is supported by the, enhanced stability of non-standard analogues containing D-Ala or D-Ser at, position 20. The crystal structure of the D-Ala20 analogue, determined to, a resolution of 1.4 A, is essentially identical to the wild-type structure, in the same crystal form. The mean root-mean-square deviation between, equivalent C(alpha) atoms (residues 5-28) is 0.3 A; (phi, psi) angles of, D-Ala20 are the same as those of G20 in the wild-type structure. Whereas, the side-chain of A20 or R20 would be expected to clash with the preceding, carbonyl oxygen (thus accounting for its frustrated energy landscape), the, side-chain of D-Ala20 projects into solvent without perturbation of the, Schellman motif. Calorimetric studies indicate that the increased, stability of the D-Ala20 analogue (DeltaDeltaG(u) 1.5 kcal/mol) is, entropic in origin, consistent with a conformational bias toward, native-like conformations in the unfolded state. Studies of multiple, substitutions at G20 and neighboring positions highlight the essential, contributions of a glycine-specific tight turn and adjoining inter-subunit, side-chain hydrogen bonds to the stability and architectural specificity, of the intertwined dimer. Comparison of L- and D amino acid substitutions, thus provides an example of the stereospecific control of an energy, landscape by a helix-capping residue.

Disease

Known diseases associated with this structure: Diabetes mellitus, insulin-dependent OMIM:[142410], Diabetes mellitus, noninsulin-dependent, 2 OMIM:[142410], Hepatic adenoma OMIM:[142410], MODY, type III OMIM:[142410]

About this Structure

2GYP is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.

Reference

Diabetes mellitus due to misfolding of a beta-cell transcription factor: stereospecific frustration of a Schellman motif in HNF-1alpha., Narayana N, Phillips NB, Hua QX, Jia W, Weiss MA, J Mol Biol. 2006 Sep 22;362(3):414-29. Epub 2006 Jul 27. PMID:16930618

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