PDBsum entry 2mpi

Protein binding

PDB id: 2mpi

Contents

Protein chains

21 a.a.

30 a.a.

PDB id:

2mpi

Name:

Protein binding

Title:

Solution structure of b24g insulin

Structure:

Insulin chain a. Chain: a. Engineered: yes. Mutation: yes. Insulin chain b. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ins. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

NMR struc:

18 models

Authors:

Y.Yang,N.P.Wickramasinghe,Q.Hua,M.A.Weiss

Key ref:

J.G.Menting et al. (2014). Protective hinge in insulin opens to enable its receptor engagement. Proc Natl Acad Sci U S A, 111, E3395. PubMed id: 25092300 DOI: 10.1073/pnas.1412897111

Date:

19-May-14 Release date: 24-Dec-14

Protein chain

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 21 a.a.

Protein chain

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 30 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1073/pnas.1412897111

Proc Natl Acad Sci U S A 111:E3395 (2014)

PubMed id: 25092300

Protective hinge in insulin opens to enable its receptor engagement.

J.G.Menting, Y.Yang, S.J.Chan, N.B.Phillips, B.J.Smith, J.Whittaker, N.P.Wickramasinghe, L.J.Whittaker, V.Pandyarajan, Z.L.Wan, S.P.Yadav, J.M.Carroll, N.Strokes, C.T.Roberts, F.Ismail-Beigi, W.Milewski, D.F.Steiner, V.S.Chauhan, C.W.Ward, M.A.Weiss, M.C.Lawrence.

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.