2naw

From Proteopedia

(Difference between revisions)

Current revision

NMR solution structure of Exendin-4/conotoxin chimera (Ex-4[1-27]/pl14a)

Structural highlights

2naw is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CJEA_CONPO 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

Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide alpha-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fraction helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe22 into a hydrophobic pocket on the GLP-1R.

Truncated glucagon-like peptide-1 and exendin-4 alpha-conotoxin pl14a peptide chimeras maintain potency, alpha-helicity and reveal interactions vital for cAMP signaling in vitro.,Swedberg JE, Schroeder CI, Mitchell J, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ J Biol Chem. 2016 May 10. pii: jbc.M116.724542. PMID:27226591^[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
↑ Swedberg JE, Schroeder CI, Mitchell J, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ. Truncated glucagon-like peptide-1 and exendin-4 alpha-conotoxin pl14a peptide chimeras maintain potency, alpha-helicity and reveal interactions vital for cAMP signaling in vitro. J Biol Chem. 2016 May 10. pii: jbc.M116.724542. PMID:27226591 doi:http://dx.doi.org/10.1074/jbc.M116.724542

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/2naw"

Categories: Large Structures | Craik DJ | Schroeder CI | Swedberg JE

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 2naw is ON HOLD
+==NMR solution structure of Exendin-4/conotoxin chimera (Ex-4[1-27]/pl14a)==
+<StructureSection load='2naw' size='340' side='right'caption='[[2naw]]' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2naw]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NAW FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=2naw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2naw OCA], [https://pdbe.org/2naw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2naw RCSB], [https://www.ebi.ac.uk/pdbsum/2naw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2naw ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CJEA_CONPO CJEA_CONPO] [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 ==
+Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide alpha-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fraction helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe22 into a hydrophobic pocket on the GLP-1R.
-Authors: Schroeder, C.I., Swedberg, J.E., Craik, D.J.
+Truncated glucagon-like peptide-1 and exendin-4 alpha-conotoxin pl14a peptide chimeras maintain potency, alpha-helicity and reveal interactions vital for cAMP signaling in vitro.,Swedberg JE, Schroeder CI, Mitchell J, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ J Biol Chem. 2016 May 10. pii: jbc.M116.724542. PMID:27226591<ref>PMID:27226591</ref>
-Description: Ex-4[1-27]/pl14a
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Swedberg, J.E]]
+<div class="pdbe-citations 2naw" style="background-color:#fffaf0;"></div>
-[[Category: Schroeder, C.I]]
+== References ==
-[[Category: Craik, D.J]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Craik DJ]]
+[[Category: Schroeder CI]]
+[[Category: Swedberg JE]]

2naw

From Proteopedia

Current revision

NMR solution structure of Exendin-4/conotoxin chimera (Ex-4[1-27]/pl14a)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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