1zeh
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STRUCTURE OF INSULIN
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this StructureAbout this Structure
1ZEH is a Protein complex structure of sequences from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues., Whittingham JL, Edwards DJ, Antson AA, Clarkson JM, Dodson GG, Biochemistry. 1998 Aug 18;37(33):11516-23. PMID:9708987
Page seeded by OCA on Fri Feb 15 17:13:12 2008