2mpi

Solution structure of B24G insulinSolution structure of B24G insulin

Structural highlights 2mpi is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 18 models Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal B-chain segment, critical for protective self-assembly in beta cells and receptor binding at target tissues. Insight may be obtained from truncated "microreceptors" that reconstitute the primary hormone-binding site (alpha-subunit domains L1 and alphaCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 beta-turn, coupling reorientation of PheB24 to a 60 degrees rotation of the B25-B28 beta-strand away from the hormone core to lie antiparallel to the receptor's L1-beta2 sheet. Opening of this hinge enables conserved nonpolar side chains (IleA2, ValA3, ValB12, PheB24, and PheB25) to engage the receptor. Restraining the hinge by nonstandard mutagenesis preserves native folding but blocks receptor binding, whereas its engineered opening maintains activity at the price of protein instability and nonnative aggregation. Our findings rationalize properties of clinical mutations in the insulin family and provide a previously unidentified foundation for designing therapeutic analogs. We envisage that a switch between free and receptor-bound conformations of insulin evolved as a solution to conflicting structural determinants of biosynthesis and function. Protective hinge in insulin opens to enable its receptor engagement.,Menting JG, Yang Y, Chan SJ, Phillips NB, Smith BJ, Whittaker J, Wickramasinghe NP, Whittaker LJ, Pandyarajan V, Wan ZL, Yadav SP, Carroll JM, Strokes N, Roberts CT Jr, Ismail-Beigi F, Milewski W, Steiner DF, Chauhan VS, Ward CW, Weiss MA, Lawrence MC Proc Natl Acad Sci U S A. 2014 Aug 4. pii: 201412897. PMID:25092300 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin 3D Structures

spinqualitylabelsall models 2mpi Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image