2h8r

From Proteopedia

(Difference between revisions)

Revision as of 11:14, 3 October 2014

Hepatocyte Nuclear Factor 1b bound to DNA: MODY5 Gene Product

Structural highlights

2h8r is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[HNF1B_HUMAN] Defects in HNF1B are the cause of renal cysts and diabetes syndrome (RCAD) [MIM:137920]; also called maturity-onset diabetes of the young type 5 (MODY5) or familial hypoplastic glomerulocystic kidney disease (GCKD). RCAD is an autosomal dominant disorder comprising non-diabetic renal disease resulting from abnormal renal development, and diabetes, which in some cases occurs earlier than age 25 years and is thus consistent with a diagnosis of maturity-onset diabetes of the young (MODY5). The renal disease is highly variable and includes renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelves, abnormal calyces, small kidney, single kidney, horseshoe kidney, and hyperuricemic nephropathy.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] Defects in HNF1B may be rare genetic risk factor contributing to the development of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.^[11] Defects in HNF1B may be a cause of susceptibility to prostate cancer hereditary type 11 (HPC11) [MIM:611955]. It is a condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma.

Function

[HNF1B_HUMAN] Transcription factor, probably binds to the inverted palindrome 5'-GTTAATNATTAAC-3'.

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 PubMed

HNF1beta is an atypical POU transcription factor that participates in a hierarchical network of transcription factors controlling the development and proper function of vital organs such as liver, pancreas, and kidney. Many inheritable mutations on HNF1beta are the monogenic causes of diabetes and several kidney diseases. To elucidate the molecular mechanism of its function and the structural basis of mutations, we have determined the crystal structure of human HNF1beta DNA binding domain in complex with a high-affinity promoter. Disease-causing mutations have been mapped to our structure, and their predicted effects have been tested by a set of biochemical/ functional studies. These findings together with earlier findings with a homologous protein HNF1alpha, help us to understand the structural basis of promoter recognition by these atypical POU transcription factors and the site-specific functional disruption by disease-causing mutations.

Structural basis of disease-causing mutations in hepatocyte nuclear factor 1beta.,Lu P, Rha GB, Chi YI Biochemistry. 2007 Oct 30;46(43):12071-80. Epub 2007 Oct 9. PMID:17924661^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet. 1999 Oct;8(11):2001-8. PMID:10484768
↑ Weng JP, Lehto M, Forsblom C, Huang X, Li H, Groop LC. Hepatocyte nuclear factor-1 beta (MODY5) gene mutations in Scandinavian families with early-onset diabetes or kidney disease or both. Diabetologia. 2000 Jan;43(1):131-2. PMID:10672455
↑ Yoshiuchi I, Yamagata K, Zhu Q, Tamada I, Takahashi Y, Onigata K, Takeda J, Miyagawa J, Matsuzawa Y. Identification of a gain-of-function mutation in the HNF-1beta gene in a Japanese family with MODY. Diabetologia. 2002 Jan;45(1):154-5. PMID:11845238 doi:10.1007/s001250200020
↑ Bingham C, Ellard S, Cole TR, Jones KE, Allen LI, Goodship JA, Goodship TH, Bakalinova-Pugh D, Russell GI, Woolf AS, Nicholls AJ, Hattersley AT. Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1beta mutations. Kidney Int. 2002 Apr;61(4):1243-51. PMID:11918730 doi:10.1046/j.1523-1755.2002.00272.x
↑ So WY, Ng MC, Horikawa Y, Njolstad PR, Li JK, Ma RC, Bell GI, Chan JC. Genetic variants of hepatocyte nuclear factor-1beta in Chinese young-onset diabetic patients with nephropathy. J Diabetes Complications. 2003 Nov-Dec;17(6):369-73. PMID:14583183
↑ Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004 Apr 6;140(7):510-7. PMID:15068978
↑ Kitanaka S, Miki Y, Hayashi Y, Igarashi T. Promoter-specific repression of hepatocyte nuclear factor (HNF)-1 beta and HNF-1 alpha transcriptional activity by an HNF-1 beta missense mutant associated with Type 5 maturity-onset diabetes of the young with hepatic and biliary manifestations. J Clin Endocrinol Metab. 2004 Mar;89(3):1369-78. PMID:15001636
↑ Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab. 2004 Jun;89(6):2905-8. PMID:15181075 doi:10.1210/jc.2003-031828
↑ Bellanne-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, Douillard C, Dubois-Laforgue D, Dusselier L, Gautier JF, Jadoul M, Laloi-Michelin M, Jacquesson L, Larger E, Louis J, Nicolino M, Subra JF, Wilhem JM, Young J, Velho G, Timsit J. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 2005 Nov;54(11):3126-32. PMID:16249435
↑ Edghill EL, Bingham C, Ellard S, Hattersley AT. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet. 2006 Jan;43(1):84-90. Epub 2005 Jun 1. PMID:15930087 doi:10.1136/jmg.2005.032854
↑ Furuta H, Furuta M, Sanke T, Ekawa K, Hanabusa T, Nishi M, Sasaki H, Nanjo K. Nonsense and missense mutations in the human hepatocyte nuclear factor-1 beta gene (TCF2) and their relation to type 2 diabetes in Japanese. J Clin Endocrinol Metab. 2002 Aug;87(8):3859-63. PMID:12161522
↑ Lu P, Rha GB, Chi YI. Structural basis of disease-causing mutations in hepatocyte nuclear factor 1beta. Biochemistry. 2007 Oct 30;46(43):12071-80. Epub 2007 Oct 9. PMID:17924661 doi:10.1021/bi7010527

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2h8r"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_2h8r|  PDB=2h8r  |  SCENE=  }}
+==Hepatocyte Nuclear Factor 1b bound to DNA: MODY5 Gene Product==
-===Hepatocyte Nuclear Factor 1b bound to DNA: MODY5 Gene Product===
+<StructureSection load='2h8r' size='340' side='right' caption='[[2h8r]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
-{{ABSTRACT_PUBMED_17924661}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2h8r]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H8R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2H8R FirstGlance]. <br>
-==Disease==
+</td></tr><tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2h8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h8r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2h8r RCSB], [http://www.ebi.ac.uk/pdbsum/2h8r PDBsum]</span></td></tr>
-[[http://www.uniprot.org/uniprot/HNF1B_HUMAN HNF1B_HUMAN]] Defects in HNF1B are the cause of renal cysts and diabetes syndrome (RCAD) [MIM:[http://omim.org/entry/137920 137920]]; also called maturity-onset diabetes of the young type 5 (MODY5) or familial hypoplastic glomerulocystic kidney disease (GCKD). RCAD is an autosomal dominant disorder comprising non-diabetic renal disease resulting from abnormal renal development, and diabetes, which in some cases occurs earlier than age 25 years and is thus consistent with a diagnosis of maturity-onset diabetes of the young (MODY5). The renal disease is highly variable and includes renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelves, abnormal calyces, small kidney, single kidney, horseshoe kidney, and hyperuricemic nephropathy.<ref>PMID:10484768</ref><ref>PMID:10672455</ref><ref>PMID:11845238</ref><ref>PMID:11918730</ref><ref>PMID:14583183</ref><ref>PMID:15068978</ref><ref>PMID:15001636</ref><ref>PMID:15181075</ref><ref>PMID:16249435</ref><ref>PMID:15930087</ref>  Defects in HNF1B may be rare genetic risk factor contributing to the development of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.<ref>PMID:12161522</ref>  Defects in HNF1B may be a cause of susceptibility to prostate cancer hereditary type 11 (HPC11) [MIM:[http://omim.org/entry/611955 611955]]. It is a condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma.
+<table>
+== Disease ==
-==Function==
+[[http://www.uniprot.org/uniprot/HNF1B_HUMAN HNF1B_HUMAN]] Defects in HNF1B are the cause of renal cysts and diabetes syndrome (RCAD) [MIM:[http://omim.org/entry/137920 137920]]; also called maturity-onset diabetes of the young type 5 (MODY5) or familial hypoplastic glomerulocystic kidney disease (GCKD). RCAD is an autosomal dominant disorder comprising non-diabetic renal disease resulting from abnormal renal development, and diabetes, which in some cases occurs earlier than age 25 years and is thus consistent with a diagnosis of maturity-onset diabetes of the young (MODY5). The renal disease is highly variable and includes renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelves, abnormal calyces, small kidney, single kidney, horseshoe kidney, and hyperuricemic nephropathy.<ref>PMID:10484768</ref> <ref>PMID:10672455</ref> <ref>PMID:11845238</ref> <ref>PMID:11918730</ref> <ref>PMID:14583183</ref> <ref>PMID:15068978</ref> <ref>PMID:15001636</ref> <ref>PMID:15181075</ref> <ref>PMID:16249435</ref> <ref>PMID:15930087</ref>   Defects in HNF1B may be rare genetic risk factor contributing to the development of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.<ref>PMID:12161522</ref>   Defects in HNF1B may be a cause of susceptibility to prostate cancer hereditary type 11 (HPC11) [MIM:[http://omim.org/entry/611955 611955]]. It is a condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma.
+== Function ==
 [[http://www.uniprot.org/uniprot/HNF1B_HUMAN HNF1B_HUMAN]] Transcription factor, probably binds to the inverted palindrome 5'-GTTAATNATTAAC-3'.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h8/2h8r_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+HNF1beta is an atypical POU transcription factor that participates in a hierarchical network of transcription factors controlling the development and proper function of vital organs such as liver, pancreas, and kidney. Many inheritable mutations on HNF1beta are the monogenic causes of diabetes and several kidney diseases. To elucidate the molecular mechanism of its function and the structural basis of mutations, we have determined the crystal structure of human HNF1beta DNA binding domain in complex with a high-affinity promoter. Disease-causing mutations have been mapped to our structure, and their predicted effects have been tested by a set of biochemical/ functional studies. These findings together with earlier findings with a homologous protein HNF1alpha, help us to understand the structural basis of promoter recognition by these atypical POU transcription factors and the site-specific functional disruption by disease-causing mutations.
-==About this Structure==
+Structural basis of disease-causing mutations in hepatocyte nuclear factor 1beta.,Lu P, Rha GB, Chi YI Biochemistry. 2007 Oct 30;46(43):12071-80. Epub 2007 Oct 9. PMID:17924661<ref>PMID:17924661</ref>
-[[2h8r]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H8R OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<ref group="xtra">PMID:017924661</ref><references group="xtra"/><references/>
+</div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
 [[Category: Chi, Y I.]]

2h8r

From Proteopedia

Revision as of 11:14, 3 October 2014

Hepatocyte Nuclear Factor 1b bound to DNA: MODY5 Gene Product

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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