PDBsum entry 4oga

Hormone receptor/hormone/immune system

PDB id: 4oga

Contents

Protein chains

21 a.a.

21 a.a.

118 a.a.

114 a.a.

288 a.a.

15 a.a.

Ligands

NAG-NAG-BMA-MAN

NAG-NAG-BMA-FUC

NAG ×3

PDB id:

4oga

Name:

Hormone receptor/hormone/immune system

Title:

Insulin in complex with site 1 of the human insulin receptor

Structure:

Insulin a chain. Chain: a. Fragment: unp residues 90-110. Synonym: insulin b chain, insulin a chain. Engineered: yes. Insulin b chain. Chain: b. Fragment: unp residues 25-54. Synonym: insulin b chain, insulin a chain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ins. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Mus musculus. Mouse. Organism_taxid: 10090.

Resolution:

3.50Å R-factor: 0.265 R-free: 0.284

Authors:

M.C.Lawrence,J.G.Menting

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:

15-Jan-14 Release date: 27-Aug-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: 21 a.a.

Protein chain

No UniProt id for this chain

Struc: 118 a.a.

Protein chain

No UniProt id for this chain

Struc: 114 a.a.

Protein chain

P06213  (INSR_HUMAN) -  Insulin receptor from Homo sapiens

Seq: 1382 a.a.

Struc: 288 a.a.*

Protein chain

P06213  (INSR_HUMAN) -  Insulin receptor from Homo sapiens

Seq: 1382 a.a.

Struc: 15 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains E, F: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = NAG) matches with 41.38% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

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.