4OGA

Insulin in complex with Site 1 of the human insulin receptor

Summary for 4OGA

• Entry DOI: 10.2210/pdb4oga/pdb
• Related: 3W11 3W12 3W13
• Descriptor: Insulin A chain, Insulin B chain, monoclonal antibody fab 83-7 fragment - heavy chain, ... (9 entities in total)
• Functional Keywords: cell surface receptor/immune system, insulin receptor, ct peptide, insulin, hormone receptor-hormone-immune system complex, hormone receptor/hormone/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 71687.23

Authors

Lawrence, M.C.,Menting, J.G. (deposition date: 2014-01-15, release date: 2014-08-27, Last modification date: 2024-11-06)

Primary citation

Menting, J.G.,Yang, Y.,Chan, S.J.,Phillips, N.B.,Smith, B.J.,Whittaker, J.,Wickramasinghe, N.P.,Whittaker, L.J.,Pandyarajan, V.,Wan, Z.L.,Yadav, S.P.,Carroll, J.M.,Strokes, N.,Roberts, C.T.,Ismail-Beigi, F.,Milewski, W.,Steiner, D.F.,Chauhan, V.S.,Ward, C.W.,Weiss, M.A.,Lawrence, M.C.
Protective hinge in insulin opens to enable its receptor engagement.
Proc.Natl.Acad.Sci.USA, 111:E3395-E3404, 2014

PubMed Abstract: 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 β cells and receptor binding at target tissues. Insight may be obtained from truncated "microreceptors" that reconstitute the primary hormone-binding site (α-subunit domains L1 and αCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 β-turn, coupling reorientation of Phe(B24) to a 60° rotation of the B25-B28 β-strand away from the hormone core to lie antiparallel to the receptor's L1-β2 sheet. Opening of this hinge enables conserved nonpolar side chains (Ile(A2), Val(A3), Val(B12), Phe(B24), and Phe(B25)) 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.

PubMed: 25092300
DOI: 10.1073/pnas.1412897111

Experimental method

X-RAY DIFFRACTION (3.5 Å)