6ge2

From Proteopedia

(Difference between revisions)

Current revision

exendin-4 based dual GLP-1/glucagon receptor agonist

Structural highlights

6ge2 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.
Method:	Solution NMR, 10 models
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

Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design & synthesis, experimental activity and solubility profiling, a candidate molecule was identified. Novel SAR points are reported that allowed to fine-tune the desired receptor activity ratio and increased solubility in the presence of antimicrobial preservatives - findings which can be of general applicability for any peptide discovery project. The peptide was evaluated in chronic in vivo studies in obese diabetic monkeys as translational model for the human situation and demonstrated favorable blood glucose and body weight lowering effects.

Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multi-dose Formulations.,Evers A, Bossart M, Pfeiffer-Marek S, Elvert R, Schreuder HA, Kurz M, Stengelin S, Lorenz M, Herling A, Konkar AA, Lukasczyk U, Pfenninger A, Lorenz K, Haack T, Kadereit D, Wagner M J Med Chem. 2018 Jun 7. doi: 10.1021/acs.jmedchem.8b00292. PMID:29879354^[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, Bossart M, Pfeiffer-Marek S, Elvert R, Schreuder HA, Kurz M, Stengelin S, Lorenz M, Herling A, Konkar AA, Lukasczyk U, Pfenninger A, Lorenz K, Haack T, Kadereit D, Wagner M. Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multi-dose Formulations. J Med Chem. 2018 Jun 7. doi: 10.1021/acs.jmedchem.8b00292. PMID:29879354 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00292

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/6ge2"

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

@@ Line 1: / Line 1: @@
 ==exendin-4 based dual GLP-1/glucagon receptor agonist==
-<StructureSection load='6ge2' size='340' side='right'caption='[[6ge2]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
+<StructureSection load='6ge2' size='340' side='right'caption='[[6ge2]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ge2]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GE2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GE2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ge2]] 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=6GE2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6GE2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EVT:(2~{S})-2-[[(4~{S})-4-(hexadecanoylamino)-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]pentanedioic+acid'>EVT</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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AIB:ALPHA-AMINOISOBUTYRIC+ACID'>AIB</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AIB:ALPHA-AMINOISOBUTYRIC+ACID'>AIB</scene>, <scene name='pdbligand=EVT:(2~{S})-2-[[(4~{S})-4-(hexadecanoylamino)-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]pentanedioic+acid'>EVT</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ge2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ge2 OCA], [http://pdbe.org/6ge2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ge2 RCSB], [http://www.ebi.ac.uk/pdbsum/6ge2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ge2 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=6ge2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ge2 OCA], [https://pdbe.org/6ge2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ge2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ge2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ge2 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 23: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Heloderma suspectum]]
 [[Category: Large Structures]]
-[[Category: Evers, A]]
+[[Category: Evers A]]
-[[Category: Kurz, M]]
+[[Category: Kurz M]]
-[[Category: Hormone]]

6ge2

From Proteopedia

Current revision

exendin-4 based dual GLP-1/glucagon receptor agonist

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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