|
|
| (3 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Designed Exendin-4 analogues== | | ==Designed Exendin-4 analogues== |
| - | <StructureSection load='2mj9' size='340' side='right'caption='[[2mj9]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''> | + | <StructureSection load='2mj9' size='340' side='right'caption='[[2mj9]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2mj9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Gila_monster Gila monster]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MJ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MJ9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2mj9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Heloderma_suspectum Heloderma suspectum]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MJ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MJ9 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DAL:D-ALANINE'>DAL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 10 models</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1jrj|1jrj]]</div></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></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=2mj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mj9 OCA], [https://pdbe.org/2mj9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mj9 RCSB], [https://www.ebi.ac.uk/pdbsum/2mj9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mj9 ProSAT]</span></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=2mj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mj9 OCA], [https://pdbe.org/2mj9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mj9 RCSB], [https://www.ebi.ac.uk/pdbsum/2mj9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mj9 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/EXE4_HELSU EXE4_HELSU] Venom protein that mimics the incretin hormone glucagon-like peptide 1 (GLP-1). It stimulates insulin synthesis and secretion, protects against beta-cell apoptosis in response to different insults, and promotes beta-cell proliferation. It also promotes satiety, reduces food intake, reduces fat deposition, reduces body weight and inhibits gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces hypotension that is mediated by relaxation of cardiac smooth muscle.<ref>PMID:8405712</ref> <ref>PMID:19837656</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 23: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Gila monster]] | + | [[Category: Heloderma suspectum]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Farkas, V]] | + | [[Category: Farkas V]] |
| - | [[Category: Hegyi, O]] | + | [[Category: Hegyi O]] |
| - | [[Category: Jermendy, A]] | + | [[Category: Jermendy A]] |
| - | [[Category: Perczel, A]] | + | [[Category: Perczel A]] |
| - | [[Category: Rovo, P]] | + | [[Category: Rovo P]] |
| - | [[Category: Straner, P]] | + | [[Category: Straner P]] |
| - | [[Category: Szabo, M]] | + | [[Category: Szabo M]] |
| - | [[Category: Toth, G K]] | + | [[Category: Toth GK]] |
| - | [[Category: Alpha helix]]
| + | |
| - | [[Category: Toxin]]
| + | |
| - | [[Category: Trp-cage]]
| + | |
| Structural highlights
Function
EXE4_HELSU Venom protein that mimics the incretin hormone glucagon-like peptide 1 (GLP-1). It stimulates insulin synthesis and secretion, protects against beta-cell apoptosis in response to different insults, and promotes beta-cell proliferation. It also promotes satiety, reduces food intake, reduces fat deposition, reduces body weight and inhibits gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces hypotension that is mediated by relaxation of cardiac smooth muscle.[1] [2]
Publication Abstract from PubMed
Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both 15N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties.
Rational Design of alpha-Helix-Stabilized Exendin-4 Analogues.,Rovo P, Farkas V, Straner P, Szabo M, Jermendy A, Hegyi O, Toth GK, Perczel A Biochemistry. 2014 May 28. PMID:24828921[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes. 1993 Nov;42(11):1678-82. PMID:8405712
- ↑ Fry BG, Roelants K, Winter K, Hodgson WC, Griesman L, Kwok HF, Scanlon D, Karas J, Shaw C, Wong L, Norman JA. Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma). Mol Biol Evol. 2010 Feb;27(2):395-407. doi: 10.1093/molbev/msp251. Epub 2009 Oct , 15. PMID:19837656 doi:http://dx.doi.org/10.1093/molbev/msp251
- ↑ Rovo P, Farkas V, Straner P, Szabo M, Jermendy A, Hegyi O, Toth GK, Perczel A. Rational Design of alpha-Helix-Stabilized Exendin-4 Analogues. Biochemistry. 2014 May 28. PMID:24828921 doi:http://dx.doi.org/10.1021/bi500033c
|
