2NAW

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

Summary for 2NAW

• Entry DOI: 10.2210/pdb2naw/pdb
• Related: 2NAV
• NMR Information: BMRB: 25949
• Descriptor: Exendin-4, Alpha/kappa-conotoxin pl14a chimera (1 entity in total)
• Functional Keywords: agonist, toxin
• Total number of polymer chains: 1
• Total formula weight: 4496.16

Authors

Schroeder, C.I.,Swedberg, J.E.,Craik, D.J. (deposition date: 2016-01-12, release date: 2016-05-18, Last modification date: 2024-10-30)

Primary citation

Swedberg, J.E.,Schroeder, C.I.,Mitchell, J.M.,Fairlie, D.P.,Edmonds, D.J.,Griffith, D.A.,Ruggeri, R.B.,Derksen, D.R.,Loria, P.M.,Price, D.A.,Liras, S.,Craik, D.J.
Truncated Glucagon-like Peptide-1 and Exendin-4 alpha-Conotoxin pl14a Peptide Chimeras Maintain Potency and alpha-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro.
J.Biol.Chem., 291:15778-15787, 2016

PubMed Abstract: 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 an 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 α-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 fractional 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 Phe(22) into a hydrophobic pocket on the GLP-1R.

PubMed: 27226591
DOI: 10.1074/jbc.M116.724542

Experimental method

SOLUTION NMR