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5niq

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exendin-4 variant with dual GLP-1 / glucagon receptor activity

Structural highlights

5niq is a 1 chain structure with sequence from Heloderma suspectum. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity. Detailed structure-activity relationship data are shown. Further modifications with unnatural and modified amino acids resulted in novel metabolically stable peptides that demonstrated a significant dose-dependent decrease in blood glucose in chronic studies in diabetic db/db mice and reduced body weight in diet-induced obese (DIO) mice. Structural analysis by NMR spectroscopy confirmed that the peptides maintain an exendin-4-like structure with its characteristic tryptophan-cage fold motif that is responsible for favorable chemical and physical stability.

Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists.,Evers A, Haack T, Lorenz M, Bossart M, Elvert R, Henkel B, Stengelin S, Kurz M, Glien M, Dudda A, Lorenz K, Kadereit D, Wagner M J Med Chem. 2017 May 25;60(10):4293-4303. doi: 10.1021/acs.jmedchem.7b00174. Epub, 2017 May 5. PMID:28448133^[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
↑ Evers A, Haack T, Lorenz M, Bossart M, Elvert R, Henkel B, Stengelin S, Kurz M, Glien M, Dudda A, Lorenz K, Kadereit D, Wagner M. Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists. J Med Chem. 2017 May 25;60(10):4293-4303. doi: 10.1021/acs.jmedchem.7b00174. Epub, 2017 May 5. PMID:28448133 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00174

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5niq"

Categories: Heloderma suspectum | Large Structures | Evers A | Kurz M

@@ Line 1: / Line 1: @@
 ==exendin-4 variant with dual GLP-1 / glucagon receptor activity==
-<StructureSection load='5niq' size='340' side='right'caption='[[5niq]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
+<StructureSection load='5niq' size='340' side='right'caption='[[5niq]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5niq]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NIQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NIQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5niq]] 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=5NIQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NIQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D6M:N-HEXADECANOYL-L-GLUTAMIC+ACID'>D6M</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D6M:N-HEXADECANOYL-L-GLUTAMIC+ACID'>D6M</scene>, <scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=5niq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5niq OCA], [https://pdbe.org/5niq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5niq RCSB], [https://www.ebi.ac.uk/pdbsum/5niq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5niq ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5niq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5niq OCA], [http://pdbe.org/5niq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5niq RCSB], [http://www.ebi.ac.uk/pdbsum/5niq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5niq ProSAT]</span></td></tr>
 </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;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Heloderma suspectum]]
 [[Category: Large Structures]]
-[[Category: Evers, A]]
+[[Category: Evers A]]
-[[Category: Kurz, M]]
+[[Category: Kurz M]]
-[[Category: Dual glp-1 / glucagon agonist]]
-[[Category: Exendin-4 analogue]]
-[[Category: Hormone]]

5niq

From Proteopedia

Current revision

exendin-4 variant with dual GLP-1 / glucagon receptor activity

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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