PDBsum entry 1zeg

Hormone

PDB id: 1zeg

Contents

Protein chains

21 a.a.

30 a.a. *

Ligands

IPH ×3

Metals

_CL ×2

_ZN ×2

Waters ×108

* Residue conservation analysis

PDB id:

1zeg

Name:

Hormone

Title:

Structure of b28 asp insulin in complex with phenol

Structure:

Insulin. Chain: a, c. Synonym: b28asp-phn. Engineered: yes. Mutation: yes. Insulin. Chain: b, d. Synonym: b28asp-phn. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Expression_system_taxid: 4932

Biol. unit:

Hetero-Dimer (from PDB file)

Resolution:

1.60Å R-factor: 0.145 R-free: 0.192

Authors:

J.L.Whittingham,E.J.Edwards,A.A.Antson,J.M.Clarkson,G.G.Dodson

Key ref:

J.L.Whittingham et al. (1998). Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues. Biochemistry, 37, 11516-11523. PubMed id: 9708987 DOI: 10.1021/bi980807s

Date:

01-May-98 Release date: 15-Jul-98

Protein chains

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 21 a.a.

Protein chains

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 30 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1021/bi980807s

Biochemistry 37:11516-11523 (1998)

PubMed id: 9708987

Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues.

J.L.Whittingham, D.J.Edwards, A.A.Antson, J.M.Clarkson, G.G.Dodson.

ABSTRACT

Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions.