1t1q
From Proteopedia
|
NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-ABA, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES
Contents |
Overview
Binding of insulin to the insulin receptor plays a central role in the, hormonal control of metabolism. Here, we investigate possible contact, sites between the receptor and the conserved non-polar surface of the, B-chain. Evidence is presented that two contiguous sites in an, alpha-helix, Val(B12) and Tyr(B16), contact the receptor. Chemical, synthesis is exploited to obtain non-standard substitutions in an, engineered monomer (DKP-insulin). Substitution of Tyr(B16) by an isosteric, photo-activatable derivative (para-azido-phenylalanine) enables efficient, cross-linking to the receptor. Such cross-linking is specific and maps to, the L1 beta-helix of the alpha-subunit. Because substitution of Val(B12), by larger side-chains markedly impairs receptor binding, cross-linking, studies at B12 were not undertaken. Structure-function relationships are, instead probed by side-chains of similar or smaller volume: respective, substitution of Val(B12) by alanine, threonine, and alpha-aminobutyric, acid leads to activities of 1(+/-0.1)%, 13(+/-6)%, and 14(+/-5)% (relative, to DKP-insulin) without disproportionate changes in negative, cooperativity. NMR structures are essentially identical with native, insulin. The absence of transmitted structural changes suggests that the, low activities of B12 analogues reflect local perturbation of a, "high-affinity" hormone-receptor contact. By contrast, because position, B16 tolerates alanine substitution (relative activity 34(+/-10)%), the, contribution of this neighboring interaction is smaller. Together, our, results support a model in which the B-chain alpha-helix, functioning as, an essential recognition element, docks against the L1 beta-helix of the, insulin receptor.
Disease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this Structure
1T1Q is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.
Reference
How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor., Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA, J Mol Biol. 2004 Aug 6;341(2):529-50. PMID:15276842
Page seeded by OCA on Mon Nov 12 19:19:07 2007
