2jmn
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| Gene: | INS (Homo sapiens) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
NMR structure of human insulin mutant His-B10-Asp, Pro-B28-Lys, Lys-B29-Pro, 20 structures
OverviewOverview
Functional surfaces of a protein are often mapped by combination of X-ray crystallography and mutagenesis. Such studies of insulin have yielded paradoxical results, suggesting that the native state is inactive and reorganizes on receptor binding. Of particular interest is the N-terminal alpha-helix of the A-chain. Does this segment function as an alpha-helix or reorganize as recently proposed in a prohormone-convertase complex? To correlate structure and function, we describe a mapping strategy based on protein design. The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human insulin) is determined at neutral pH as a template for synthesis of a novel A-chain analogue. Designed by analogy to a protein-folding intermediate, the analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced by serine. Its solution structure is remarkable for segmental unfolding of the N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The structure demonstrates that the overall orientation of the A and B chains is consistent with reorganization of the A-chain's N-terminal segment. Nevertheless, the analogue's low biological activity suggests that this segment, a site of clinical mutation causing diabetes mellitus, functions as a preformed recognition alpha-helix.
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
2JMN is a Protein complex structure of sequences from Homo sapiens. This structure supersedes the now removed PDB entries 1LNP and 1VKS. Full crystallographic information is available from OCA.
ReferenceReference
Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue., Hua QX, Hu SQ, Frank BH, Jia W, Chu YC, Wang SH, Burke GT, Katsoyannis PG, Weiss MA, J Mol Biol. 1996 Nov 29;264(2):390-403. PMID:8951384
Page seeded by OCA on Thu Mar 20 17:42:56 2008