1ZEG

STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL

Summary for 1ZEG

• Entry DOI: 10.2210/pdb1zeg/pdb
• Descriptor: INSULIN, PHENOL, ZINC ION, ... (6 entities in total)
• Functional Keywords: hormone, metabolic role, chemical activity, insulin mutant, cross-link, glucose metabolism, diabetes
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 4
• Total formula weight: 12155.31

Authors

Whittingham, J.L.,Edwards, E.J.,Antson, A.A.,Clarkson, J.M.,Dodson, G.G. (deposition date: 1998-05-01, release date: 1998-07-15, Last modification date: 2024-10-16)

Primary citation

Whittingham, J.L.,Edwards, D.J.,Antson, A.A.,Clarkson, J.M.,Dodson, G.G.
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, 1998

PubMed 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.

PubMed: 9708987
DOI: 10.1021/bi980807s

Experimental method

X-RAY DIFFRACTION (1.6 Å)