Structure and dynamics of the insulin receptor: implications for receptor activation and drug discovery

Ye, Libin; Maji, Suvrajit; Sanghera, Narinder; Gopalasingam, Piraveen; Gorbunov, Evgeniy A.; Тарасов, С. А.; Epstein, O. I.; Klein‐Seetharaman, Judith

doi:10.1016/j.drudis.2017.04.011

Cited by 34 publications

(36 citation statements)

References 82 publications

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“…This conformation thus comprises both an insulin-bound monomer and an insulin-free monomer. Comparison of these structures suggests that binding of insulin induces both the closing of the top portion of the receptor (by rigid body motion of the L1-CR-L2 portion with respect to the FnIII-1 domain) and recruitment of the α-CT helix, contrary to a previously suggested mechanism in which the insulin molecule docks to a preformed harbor containing both the L1 and α-CT elements required for binding 26 .…”

contrasting

confidence: 59%

“…The map is asymmetric and only one of the FnIII-2 sub domains is clearly visible. b , Positioning of the FnIII-2 sub domain allows for analyzing the relative position of the bound insulin (blue) and the proposed S2 site (shown as spheres, residues selected according to 26 : the insulin is between 55 and 62 Å away, and on the opposite side of the proposed S2. c , Overlay of free insulin (1ZNI) to the insulin bound to IR.…”

Section: Extended Datamentioning

confidence: 99%

“…The inter-monomer disulfide bonds 28,29 are shown as black lines; the intra-monomer “signaling bridge” 26 is shown as an orange line. b , CryoEM density map for Class 1 with the IR sub-domains fitted to the density; one monomer is yellow, the other is color coded as in a .…”

Section: Figurementioning

confidence: 99%

“…c , Schematic diagram of a possible activation mechanism for IR. The IR sub-domains color coded as in Figure 1a (solid color for the α-chain and light colors/thicker outer lines for the β-chain); the inter-monomer disulfide bonds are shown as dotted lines, the “signaling bridge” 26 as solid orange line. Binding of one insulin molecule to the apo receptor (left to middle panel) causes the L1-CR-L2 subdomains of one monomer, the FnIII-1 subdomain of the other and the α-CT helix to move to generate the binding site.…”

Section: Figurementioning

confidence: 99%

“…It is likely that following the binding of the first insulin molecule, the large shift in position of the α-CT helix causes conformational changes in the ID-α domain of both monomers. The ID-α domain is disulfide bonded to FnIII-3 (Cys647-Cys860) and this connection (so called “signaling bridge” 26 ) may induce further conformational changes in the FnIII-3 domain, thus triggering the downstream signal propagation.…”

mentioning

confidence: 99%

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Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis

Scapin

Dandey

Zhang

et al. 2018

Nature

192

235

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Summary The insulin receptor (IR) is a dimeric protein that plays a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels1,2. IR dysfunctions have been associated with many diseases, including diabetes, cancer, and Alzheimer’s1,3,4. The primary sequence has been known since the 1980s5, and is composed of an extracellular portion (ectodomain, ECD), a single transmembrane helix and an intracellular tyrosine kinase domain. Insulin binding to the dimeric ECD triggers kinase domain auto-phosphorylation and subsequent activation of downstream signaling molecules. Biochemical and mutagenesis data have identified two putative insulin binding sites (S1 and S2)6. While insulin bound to an ECD fragment containing S1 and the apo ectodomain have been characterized structurally7,8, details of insulin binding to the full receptor and the signal propagation mechanism are still not understood. Here we report single particle cryoEM reconstructions for the 1:2 (4.3 Å) and 1:1 (7.4 Å) IR ECD dimer:Insulin complexes. The symmetric 4.3 Å structure shows two insulin molecules per dimer, each bound between the Leucine-rich sub domain L1 of one monomer and the first fibronectin-like domain (FnIII-1) of the other monomer, and making extensive interactions with the α subunit C-terminal helix (α-CT helix). The 7.4 Å structure has only one similarly bound insulin per receptor dimer. The structures confirm the S1 binding interactions and define the full S2 binding site. These insulin receptor states suggest that recruitment of the α-CT helix upon binding of the first insulin changes the relative sub domain orientations and triggers downstream signal propagation.

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contrasting

confidence: 59%

Section: Extended Datamentioning

confidence: 99%