PDBsum entry 1jrj

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Hormone/growth factor PDB id
Protein chain
39 a.a. *
* Residue conservation analysis
PDB id:
Name: Hormone/growth factor
Title: Solution structure of exendin-4 in 30-vol% trifluoroethanol
Structure: Exendin-4. Chain: a. Engineered: yes
Source: Synthetic: yes. Other_details: the protein was produced using fmoc synthesis. The sequence occurs naturally in the salivary secretion of heloderma suspectum (gila monster).
NMR struc: 36 models
Authors: J.W.Neidigh,R.M.Fesinmeyer,K.S.Prickett,N.H.Andersen
Key ref:
J.W.Neidigh et al. (2001). Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochemistry, 40, 13188-13200. PubMed id: 11683627 DOI: 10.1021/bi010902s
13-Aug-01     Release date:   21-Nov-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P26349  (EXE4_HELSU) -  Exendin-4
87 a.a.
39 a.a.
Key:    PfamA domain  Secondary structure


DOI no: 10.1021/bi010902s Biochemistry 40:13188-13200 (2001)
PubMed id: 11683627  
Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states.
J.W.Neidigh, R.M.Fesinmeyer, K.S.Prickett, N.H.Andersen.
Exendin-4, a 39 amino acid peptide originally isolated from the oral secretions of the lizard Heloderma suspectum, has been shown to share certain activities with glucagon-like-peptide-1 (GLP-1), a 30 amino acid peptide. We have determined the structuring preferences of exendin-4 and GLP-1 by NMR in both the solution and dodecylphosphocholine (DPC) micelle-associated states. Based on both chemical shift deviations and the pattern of intermediate range NOEs, both peptides display significant helicity from residue 7 to residue 28 with greater fraying at the N-terminus. Thornton and Gorenstein [(1994) Biochemistry 33, 3532-3539] reported that the presence of a flexible, helix-destabilizing, glycine at residue 16 in GLP-1 was an important feature for membrane and receptor binding. Exendin-4 has a helix-favoring glutamate as residue 16. In the micelle-associated state, NMR data indicate that GLP-1 is less helical than exendin-4 due to the presence of Gly16; chemical shift deviations along the peptide sequence suggest that Gly16 serves as an N-cap for a second, more persistent, helix. In 30 vol-% trifluoroethanol (TFE), a single continuous helix is evident in a significant fraction of the GLP-1 conformers present. Exendin-4 has a more regular and less fluxional helix in both media and displays stable tertiary structure in the solution state. In the micelle-bound state of exendin-4, a single helix (residues 11-27) is observed with residues 31-39 completely disordered and undergoing rapid segmental motion. In aqueous fluoroalcohol or aqueous glycol, the Leu21-Pro38 span of exendin-4 forms a compact tertiary fold (the Trp-cage) which shields the side chain of Trp25 from solvent exposure and produces ring current shifts as large as 3 ppm. This tertiary structure is partially populated in water and fully populated in aqueous TFE. The Leu21-Pro38 segment of exendin-4 may be the smallest protein-like folding unit observed to date. When the Trp-cage forms, fraying of the exendin-4 helix occurs exclusively from the N-terminus; backbone NHs for the C-terminal residues of the helix display H/D exchange protection factors as large as 10(5) at 9 degrees C. In contrast, no tertiary structure is evident when exendin-4 binds to DPC micelles. An energetically favorable insertion of the tryptophan ring into the DPC micelle is suggested as the basis for this change. With the exception of exendin-4 in media containing fluoro alcohol cosolvents, NMR structure ensembles generated from the NOE data do not fully reflect the conformational averaging present in these systems. Secondary structure definition from chemical shift deviations may be the most appropriate treatment for peptides that lack tertiary structure.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21244372 N.Gong, A.N.Ma, L.J.Zhang, X.S.Luo, Y.H.Zhang, M.Xu, and Y.X.Wang (2011).
Site-specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity.
  Br J Pharmacol, 163, 399-412.  
19837656 B.G.Fry, K.Roelants, K.Winter, W.C.Hodgson, L.Griesman, H.F.Kwok, D.Scanlon, J.Karas, C.Shaw, L.Wong, and J.A.Norman (2010).
Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma).
  Mol Biol Evol, 27, 395-407.  
19861722 C.R.Underwood, P.Garibay, L.B.Knudsen, S.Hastrup, G.H.Peters, R.Rudolph, and S.Reedtz-Runge (2010).
Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor.
  J Biol Chem, 285, 723-730.
PDB code: 3iol
20453923 D.N.Langelaan, and J.K.Rainey (2010).
Membrane catalysis of peptide-receptor binding.
  Biochem Cell Biol, 88, 203-210.  
20799012 M.J.Moon, H.Y.Kim, S.G.Kim, J.Park, D.S.Choi, J.I.Hwang, and J.Y.Seong (2010).
Tyr1 and Ile7 of glucose-dependent insulinotropic polypeptide (GIP) confer differential ligand selectivity toward GIP and glucagon-like peptide-1 receptors.
  Mol Cells, 30, 149-154.  
20583828 T.Reiner, R.H.Kohler, C.W.Liew, J.A.Hill, J.Gaglia, R.N.Kulkarni, and R.Weissleder (2010).
Near-infrared fluorescent probe for imaging of pancreatic beta cells.
  Bioconjug Chem, 21, 1362-1368.  
19446460 C.Parthier, S.Reedtz-Runge, R.Rudolph, and M.T.Stubbs (2009).
Passing the baton in class B GPCRs: peptide hormone activation via helix induction?
  Trends Biochem Sci, 34, 303-310.  
19226627 H.R.Costantino, H.Culley, L.Chen, D.Morris, M.Houston, S.Roth, M.J.Phoenix, C.Foerder, J.S.Philo, T.Arakawa, L.Eidenschink, N.H.Andersen, G.Brandt, and S.C.Quay (2009).
Development of Calcitonin Salmon Nasal Spray: similarity of peptide formulated in chlorobutanol compared to benzalkonium chloride as preservative.
  J Pharm Sci, 98, 3691-3706.  
19596697 J.R.Cort, Z.Liu, G.M.Lee, K.N.Huggins, S.Janes, K.Prickett, and N.H.Andersen (2009).
Solution state structures of human pancreatic amylin and pramlintide.
  Protein Eng Des Sel, 22, 497-513.  
19597507 J.W.Day, N.Ottaway, J.T.Patterson, V.Gelfanov, D.Smiley, J.Gidda, H.Findeisen, D.Bruemmer, D.J.Drucker, N.Chaudhary, J.Holland, J.Hembree, W.Abplanalp, E.Grant, J.Ruehl, H.Wilson, H.Kirchner, S.H.Lockie, S.Hofmann, S.C.Woods, R.Nogueiras, P.T.Pfluger, D.Perez-Tilve, R.DiMarchi, and M.H.Tschöp (2009).
A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.
  Nat Chem Biol, 5, 749-757.  
19267450 L.J.Juszczak, and R.Z.Desamero (2009).
Extension of the tryptophan chi2,1 dihedral angle-W3 band frequency relationship to a full rotation: correlations and caveats.
  Biochemistry, 48, 2777-2787.  
19815559 Q.Chen, D.I.Pinon, L.J.Miller, and M.Dong (2009).
Molecular basis of glucagon-like peptide 1 docking to its intact receptor studied with carboxyl-terminal photolabile probes.
  J Biol Chem, 284, 34135-34144.  
19693803 Z.Gattin, S.Riniker, P.J.Hore, K.H.Mok, and W.F.van Gunsteren (2009).
Temperature and urea induced denaturation of the TRP-cage mini protein TC5b: A simulation study consistent with experimental observations.
  Protein Sci, 18, 2090-2099.  
18611374 F.Ding, D.Tsao, H.Nie, and N.V.Dokholyan (2008).
Ab initio folding of proteins with all-atom discrete molecular dynamics.
  Structure, 16, 1010-1018.  
18555686 J.M.Neumann, A.Couvineau, S.Murail, J.J.Lacapère, N.Jamin, and M.Laburthe (2008).
Class-B GPCR activation: is ligand helix-capping the key?
  Trends Biochem Sci, 33, 314-319.  
18342803 P.H.Johnson, D.Frank, and H.R.Costantino (2008).
Discovery of tight junction modulators: significance for drug development and delivery.
  Drug Discov Today, 13, 261-267.  
18287102 S.Runge, H.Thøgersen, K.Madsen, J.Lau, and R.Rudolph (2008).
Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain.
  J Biol Chem, 283, 11340-11347.
PDB codes: 3c59 3c5t
18821747 T.Yamamoto, P.Nair, N.E.Jacobsen, P.Davis, S.W.Ma, E.Navratilova, S.Moye, J.Lai, H.I.Yamamura, T.W.Vanderah, F.Porreca, and V.J.Hruby (2008).
The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists.
  J Med Chem, 51, 6334-6347.  
17393464 I.Alaña, J.P.Malthouse, F.P.O'Harte, and C.M.Hewage (2007).
The bioactive conformation of glucose-dependent insulinotropic polypeptide by NMR and CD spectroscopy.
  Proteins, 68, 92-99.
PDB code: 2obu
17326200 J.Copps, R.F.Murphy, and S.Lovas (2007).
VCD spectroscopic and molecular dynamics analysis of the Trp-cage miniprotein TC5b.
  Biopolymers, 88, 427-437.  
  17620721 P.Li, T.Rogers, D.Smiley, R.D.DiMarchi, and F.Zhang (2007).
Design, synthesis and crystallization of a novel glucagon analog as a therapeutic agent.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 599-601.  
17264074 R.E.Herman, D.Badders, M.Fuller, E.G.Makienko, M.E.Houston, S.C.Quay, and P.H.Johnson (2007).
The Trp cage motif as a scaffold for the display of a randomized peptide library on bacteriophage T7.
  J Biol Chem, 282, 9813-9824.  
16447056 L.Simonsen, J.J.Holst, and C.F.Deacon (2006).
Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs.
  Diabetologia, 49, 706-712.  
15836251 A.Linhananta, J.Boer, and I.MacKay (2005).
The equilibrium properties and folding kinetics of an all-atom Go model of the Trp-cage.
  J Chem Phys, 122, 114901.  
15533926 F.Ding, S.V.Buldyrev, and N.V.Dokholyan (2005).
Folding Trp-cage to NMR resolution native structure using a coarse-grained protein model.
  Biophys J, 88, 147-155.  
15852457 H.Hui, X.Zhao, and R.Perfetti (2005).
Structure and function studies of glucagon-like peptide-1 (GLP-1): the designing of a novel pharmacological agent for the treatment of diabetes.
  Diabetes Metab Res Rev, 21, 313-331.  
15386269 F.M.Hudson, and N.H.Andersen (2004).
Exenatide: NMR/CD evaluation of the medium dependence of conformation and aggregation state.
  Biopolymers, 76, 298-308.  
12833552 G.V.Nikiforovich, N.H.Andersen, R.M.Fesinmeyer, and C.Frieden (2003).
Possible locally driven folding pathways of TC5b, a 20-residue protein.
  Proteins, 52, 292-302.  
12808142 J.W.Pitera, and W.Swope (2003).
Understanding folding and design: replica-exchange simulations of "Trp-cage" miniproteins.
  Proc Natl Acad Sci U S A, 100, 7587-7592.  
12524435 R.López de Maturana, A.Willshaw, A.Kuntzsch, R.Rudolph, and D.Donnelly (2003).
The isolated N-terminal domain of the glucagon-like peptide-1 (GLP-1) receptor binds exendin peptides with much higher affinity than GLP-1.
  J Biol Chem, 278, 10195-10200.  
12970080 S.Al-Sabah, and D.Donnelly (2003).
A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors.
  Br J Pharmacol, 140, 339-346.  
14624865 S.Lien, and H.B.Lowman (2003).
Therapeutic peptides.
  Trends Biotechnol, 21, 556-562.  
12562773 S.T.Hsu, E.Breukink, G.Bierbaum, H.G.Sahl, Kruijff, R.Kaptein, N.A.van Nuland, and A.M.Bonvin (2003).
NMR study of mersacidin and lipid II interaction in dodecylphosphocholine micelles. Conformational changes are a key to antimicrobial activity.
  J Biol Chem, 278, 13110-13117.
PDB codes: 1mqx 1mqy 1mqz
12389215 J.W.Neidigh, and N.H.Andersen (2002).
Peptide conformational changes induced by tryptophan-phosphocholine interactions in a micelle.
  Biopolymers, 65, 354-361.  
11979279 J.W.Neidigh, R.M.Fesinmeyer, and N.H.Andersen (2002).
Designing a 20-residue protein.
  Nat Struct Biol, 9, 425-430.
PDB code: 1l2y
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