2gyp: Difference between revisions

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==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.

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==

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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16930618 16930618]

[[Category: Single protein]]

[[Category: Hua, Q.X.]]

[[Category: Hua, Q X.]]

[[Category: Jia, W.]]

[[Category: Narayana, N.]]

[[Category: Phillips, N.B.]]

[[Category: Phillips, N B.]]

[[Category: Weiss, M.A.]]

[[Category: Weiss, M A.]]

[[Category: energy landscape]]

[[Category: gene regulation]]

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[[Category: protein structure]]

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@@ Line 4: / Line 4: @@
 ==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.
+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==
@@ Line 15: / Line 15: @@
 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16930618 16930618]
 [[Category: Single protein]]
-[[Category: Hua, Q.X.]]
+[[Category: Hua, Q X.]]
 [[Category: Jia, W.]]
 [[Category: Narayana, N.]]
-[[Category: Phillips, N.B.]]
+[[Category: Phillips, N B.]]
-[[Category: Weiss, M.A.]]
+[[Category: Weiss, M A.]]
 [[Category: energy landscape]]
 [[Category: gene regulation]]
@@ Line 26: / Line 26: @@
 [[Category: protein structure]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:29:18 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:36:30 2008''