1mhj

From Proteopedia

---

Revision as of 16:04, 12 November 2007

proteopedia linkproteopedia link

spinqualitylabelsall models 1mhj Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

SOLUTION STRUCTURE OF THE SUPERACTIVE MONOMERIC DES-[PHE(B25)] HUMAN INSULIN MUTANT. ELUCIDATION OF THE STRUCTURAL BASIS FOR THE MONOMERIZATION OF THE DES-[PHE(B25)] INSULIN AND THE DIMERIZATION OF NATIVE INSULIN

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The three-dimensional solution structure of des-[Phe(B25)] human insulin, has been determined by nuclear magnetic resonance spectroscopy and, restrained molecular dynamics calculations. Thirty-five structures were, calculated by distance geometry from 581 nuclear Overhauser, enhancement-derived distance constraints, ten phi torsional angle, restraints, the restraints from 16 helical hydrogen bonds, and three, disulfide bridges. The distance geometry structures were optimized using, simulated annealing and restrained energy minimization. The average, root-mean-square (r.m.s.) deviation for the best 20 refined structures is, 1.07 angstroms for the backbone and 1.92 angstroms for all atoms if the, less well-defined N and C-terminal residues are excluded. The helical, regions are more well defined, with r.m.s. deviations of 0.64 angstroms, for the backbone and 1.51 angstroms for all atoms. It is found that the, des-[Phe(B25)] insulin is a monomer under the applied conditions (4.6 to, 4.7 mM, pH 3.0, 310 K), that the overall secondary and tertiary structures, of the monomers in the 2Zn crystal hexamer of native insulin are, preserved, and that the conformation-averaged NMR solution structure is, close to the structure of molecule 1 in the hexamer. The structure reveals, that the lost ability of des-[Phe(B25)] insulin to self-associate is, caused by a conformational change of the C-terminal region of the B-chain, which results in an intra-molecular hydrophobic interaction between, Pro(B28) and the hydrophobic region Leu(B11)-Leu(B15) of the B-chain, alpha-helix. This interaction interferes with the inter-molecular, hydrophobic interactions responsible for the dimerization of native, insulin, depriving the mutant of the ability to dimerize. Further, the, structure displays a series of features that may explain the high potency, of the mutant on the basis of the current model for the insulin-receptor, interaction. These features are: a change in conformation of the, C-terminal region of the B-chain, the absence of strong hydrogen bonds, between this region and the rest of the molecule, and a relatively easy, accessibility to the Val(A3) residue.

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

1MHJ is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Solution structure of the superactive monomeric des-[Phe(B25)] human insulin mutant: elucidation of the structural basis for the monomerization of des-[Phe(B25)] insulin and the dimerization of native insulin., Jorgensen AM, Olsen HB, Balschmidt P, Led JJ, J Mol Biol. 1996 Apr 5;257(3):684-99. PMID:8648633

Page seeded by OCA on Mon Nov 12 18:11:22 2007