2ws1: Difference between revisions

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-{{STRUCTURE_2ws1|  PDB=2ws1  |  SCENE=  }}
+==Semi-synthetic analogue of human insulin NMeTyrB26-insulin in monomer form==
-===Semi-synthetic analogue of human insulin NMeTyrB26-insulin in monomer form===
+<StructureSection load='2ws1' size='340' side='right' caption='[[2ws1]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
-{{ABSTRACT_PUBMED_20133841}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2ws1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WS1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WS1 FirstGlance]. <br>
-==Disease==
+</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene><br>
-[[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref><ref>PMID:2196279</ref><ref>PMID:4019786</ref><ref>PMID:1601997</ref>  Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 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 derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref>  Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref><ref>PMID:18162506</ref>  Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 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:18192540</ref><ref>PMID:18162506</ref><ref>PMID:20226046</ref>
+<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=YNM:N-METHYL-L-TYROSINE'>YNM</scene></td></tr>
+<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hit|1hit]], [[2hho|2hho]], [[2c8q|2c8q]], [[1tyl|1tyl]], [[2c8r|2c8r]], [[1t1k|1t1k]], [[1aiy|1aiy]], [[1xda|1xda]], [[1htv|1htv]], [[1mso|1mso]], [[1uz9|1uz9]], [[1fub|1fub]], [[1tym|1tym]], [[1hui|1hui]], [[2vk0|2vk0]], [[1vkt|1vkt]], [[1hls|1hls]], [[2ceu|2ceu]], [[1t1q|1t1q]], [[1qj0|1qj0]], [[1mhj|1mhj]], [[1fu2|1fu2]], [[1sjt|1sjt]], [[1qiy|1qiy]], [[1iog|1iog]], [[2vjz|2vjz]], [[1ioh|1ioh]], [[1trz|1trz]], [[1evr|1evr]], [[1ev3|1ev3]], [[1rwe|1rwe]], [[1os4|1os4]], [[1guj|1guj]], [[1ai0|1ai0]], [[1sf1|1sf1]], [[1jco|1jco]], [[1jca|1jca]], [[1zeg|1zeg]], [[1os3|1os3]], [[1xgl|1xgl]], [[1t0c|1t0c]], [[1qiz|1qiz]], [[1g7b|1g7b]], [[2wby|2wby]], [[2aiy|2aiy]], [[1ev6|1ev6]], [[1q4v|1q4v]], [[2hh4|2hh4]], [[2h67|2h67]], [[4aiy|4aiy]], [[1j73|1j73]], [[1k3m|1k3m]], [[1mhi|1mhi]], [[2wc0|2wc0]], [[1kmf|1kmf]], [[2hiu|2hiu]], [[1xw7|1xw7]], [[5aiy|5aiy]], [[1g7a|1g7a]], [[1znj|1znj]], [[1zeh|1zeh]], [[1his|1his]], [[1b9e|1b9e]], [[3aiy|3aiy]], [[1w8p|1w8p]], [[1hiq|1hiq]], [[1lph|1lph]], [[1efe|1efe]], [[1a7f|1a7f]], [[1t1p|1t1p]], [[1ben|1ben]], [[1lkq|1lkq]], [[2ws7|2ws7]], [[2ws0|2ws0]], [[2ws4|2ws4]], [[2ws6|2ws6]], [[2wrx|2wrx]], [[2wrw|2wrw]], [[2wru|2wru]], [[2wrv|2wrv]]</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=2ws1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ws1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ws1 RCSB], [http://www.ebi.ac.uk/pdbsum/2ws1 PDBsum]</span></td></tr>
+<table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref>   Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 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 derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref>   Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref>   Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 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:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
+== 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/ws/2ws1_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 ==
+Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin's induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200-500%) insulin analogues that are truncated at residue 26 of the B-chain (B(26)). They show a structural convergence in the form of a new beta-turn at B(24)-B(26). We propose that the key element in insulin's transition, from an inactive to an active state, may be the formation of the beta-turn at B(24)-B(26) associated with a trans to cis isomerisation at the B(25)-B(26) peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B(25)-B(26) peptide bond or by the insertion of certain D-amino acids at B(26). The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes.
-==Function==
+Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues.,Jiracek J, Zakova L, Antolikova E, Watson CJ, Turkenburg JP, Dodson GG, Brzozowski AM Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1966-70. Epub 2010 Jan 25. PMID:20133841<ref>PMID:20133841</ref>
-[[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[2ws1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WS1 OCA].
+</div>
 ==See Also==
 *[[Molecular Playground/Insulin|Molecular Playground/Insulin]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:020133841</ref><references group="xtra"/><references/>
+__TOC__
+</StructureSection>
 [[Category: Antolikova, E.]]
 [[Category: Brzozowski, A M.]]