5ems: Difference between revisions

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-'''Unreleased structure'''
-The entry 5ems is ON HOLD  until Paper Publication
+==Crystal Structure of an iodinated insulin analog==
+<StructureSection load='5ems' size='340' side='right'caption='[[5ems]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5ems]] is a 12 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=5EMS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EMS FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IPH:PHENOL'>IPH</scene>, <scene name='pdbligand=IYR:3-IODO-TYROSINE'>IYR</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5ems FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ems OCA], [https://pdbe.org/5ems PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ems RCSB], [https://www.ebi.ac.uk/pdbsum/5ems PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ems ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[https://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:[https://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:[https://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:[https://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 ==
+[https://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.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (TyrB26) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomic-level simulations of 3-I-TyrB26-insulin to predict its structural features and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog - as a dimer and hexamer - exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings at this interface (TyrB16, PheB24, PheB25, 3-I-TyrB26 and their symmetry-related mates) adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-iodo-TyrB26 insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-TyrB26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-TyrB26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient sigma-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins.
-Authors: Lawrence, M.C., Pandyarajan, V., Wan, Z., Weiss, M.A.
+Extending Halogen-Based Medicinal Chemistry to Proteins: Iodo-Insulin as a Case Study.,El Hage K, Pandyarajan V, Phillips NB, Smith BJ, Menting JG, Whittaker J, Lawrence MC, Meuwly M, Weiss MA J Biol Chem. 2016 Nov 14. pii: jbc.M116.761015. PMID:27875310<ref>PMID:27875310</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Weiss, M.A]]
+<div class="pdbe-citations 5ems" style="background-color:#fffaf0;"></div>
-[[Category: Wan, Z]]
-[[Category: Lawrence, M.C]]
+==See Also==
-[[Category: Pandyarajan, V]]
+*[[Insulin 3D Structures|Insulin 3D Structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Lawrence MC]]
+[[Category: Pandyarajan V]]
+[[Category: Wan Z]]
+[[Category: Weiss MA]]