PDBsum entry 2mj9

Toxin

PDB id: 2mj9

Contents

Protein chain

39 a.a.

PDB id:

2mj9

Name:

Toxin

Title:

Designed exendin-4 analogues

Structure:

Exendin-4. Chain: a. Engineered: yes

Source:

Heloderma suspectum. Gila monster. Organism_taxid: 8554. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

10 models

Authors:

P.Rovo,V.Farkas,P.Straner,M.Szabo,A.Jermendy,O.Hegyi,G.K.Toth, A.Perczel

Key ref:

P.Rovó et al. (2014). Rational design of α-helix-stabilized exendin-4 analogues. Biochemistry, 53, 3540-3552. PubMed id: 24828921 DOI: 10.1021/bi500033c

Date:

30-Dec-13 Release date: 04-Jun-14

Protein chain

P26349  (EXE4_HELSU) -  Exendin-4 from Heloderma suspectum

Seq: 87 a.a.

Struc: 39 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1021/bi500033c

Biochemistry 53:3540-3552 (2014)

PubMed id: 24828921

Rational design of α-helix-stabilized exendin-4 analogues.

P.Rovó, V.Farkas, P.Stráner, M.Szabó, A.Jermendy, O.Hegyi, G.K.Tóth, A.Perczel.

ABSTRACT

Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both (15)N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties.