View source for 2gyp


==Diabetes mellitus due to a frustrated Schellman motif in HNF-1a==
<StructureSection load='2gyp' size='340' side='right'caption='[[2gyp]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2gyp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GYP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GYP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2gyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gyp OCA], [https://pdbe.org/2gyp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gyp RCSB], [https://www.ebi.ac.uk/pdbsum/2gyp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gyp ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HNF1A_HUMAN HNF1A_HUMAN] Defects in HNF1A are a cause of hepatic adenomas familial (HEPAF) [MIM:[https://omim.org/entry/142330 142330]. Hepatic adenomas are rare benign liver tumors of presumable epithelial origin that develop in an otherwise normal liver. Hepatic adenomas may be single or multiple. They consist of sheets of well-differentiated hepatocytes that contain fat and glycogen and can produce bile. Bile ducts or portal areas are absent. Kupffer cells, if present, are reduced in number and are non-functional. Conditions associated with adenomas are insulin-dependent diabetes mellitus and glycogen storage diseases (types 1 and 3). Note=Bi-allelic inactivation of HNF1A, whether sporadic or associated with MODY3, may be an early step in the developmant of some hepatocellular carcinomas.  Defects in HNF1A are the cause of maturity-onset diabetes of the young type 3 (MODY3) [MIM:[https://omim.org/entry/600496 600496]; also symbolized MODY-3. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:12453420</ref> <ref>PMID:10966642</ref> <ref>PMID:8945470</ref> <ref>PMID:9166684</ref> <ref>PMID:9287053</ref> <ref>PMID:9392505</ref> <ref>PMID:9032114</ref> <ref>PMID:9075818</ref> <ref>PMID:9075819</ref> <ref>PMID:9097962</ref> <ref>PMID:9754819</ref> <ref>PMID:9626139</ref> <ref>PMID:10078571</ref> <ref>PMID:10102714</ref> <ref>PMID:10588527</ref> <ref>PMID:10482964</ref>   Defects in HNF1A are the cause of susceptibility to diabetes mellitus insulin-dependent type 20 (IDDM20) [MIM:[https://omim.org/entry/612520 612520]. IDDM20 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These features can result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:9313763</ref> <ref>PMID:9867222</ref> <ref>PMID:10333057</ref> 
== Function ==
[https://www.uniprot.org/uniprot/HNF1A_HUMAN HNF1A_HUMAN] Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver. Required for the expression of several liver specific genes. Binds to the inverted palindrome 5'-GTTAATNATTAAC-3'.<ref>PMID:12453420</ref> <ref>PMID:10966642</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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<ref>PMID:16930618</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2gyp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hua QX]]
[[Category: Jia W]]
[[Category: Narayana N]]
[[Category: Phillips NB]]
[[Category: Weiss MA]]