2gyp
From Proteopedia
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[[Image:2gyp.jpg|left|200px]] | [[Image:2gyp.jpg|left|200px]] | ||
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'''Diabetes mellitus due to a frustrated Schellman motif in HNF-1a''' | '''Diabetes mellitus due to a frustrated Schellman motif in HNF-1a''' | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2GYP is a [[Single protein]] structure | + | 2GYP is a [[Single protein]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GYP OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Phillips, N B.]] | [[Category: Phillips, N B.]] | ||
[[Category: Weiss, M A.]] | [[Category: Weiss, M A.]] | ||
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| - | [[Category: | + | [[Category: Gene regulation]] |
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| - | [[Category: | + | [[Category: Protein stability]] |
| - | [[Category: | + | [[Category: Protein structure]] |
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Revision as of 02:39, 4 May 2008
Diabetes mellitus due to a frustrated Schellman motif in HNF-1a
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.
About this Structure
2GYP is a Single protein structure. 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 Page seeded by OCA on Sun May 4 05:39:35 2008
