Dataset Information

Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor.

ABSTRACT: Sets of synthetic peptides that interact with the insulin receptor ectodomain have been discovered by phage display and reported in the literature. These peptides were grouped into three classes termed Site 1, Site 2, and Site 3 based on their mutual competition of binding to the receptor. Further refinement has yielded, in particular, a 36-residue Site 2-Site 1 fusion peptide, S519, that binds the insulin receptor with subnanomolar affinity and exhibits agonist activity in both lipogenesis and glucose uptake assays. Here, we report three-dimensional crystallographic detail of the interaction of the C-terminal, 16-residue Site 1 component (S519C16) of S519 with the first leucine-rich repeat domain (L1) of the insulin receptor. Our structure shows that S519C16 binds to the same site on the L1 surface as that occupied by a critical component of the primary binding site, namely the helical C-terminal segment of the insulin receptor ?-chain (termed ?CT). In particular, the two phenylalanine residues within the FYXWF motif of S519C16 are seen to engage the insulin receptor L1 domain surface in a fashion almost identical to the respective ?CT residues Phe(701) and Phe(705) The structure provides a platform for the further development of peptidic and/or small molecule agents directed toward the insulin receptor and/or the type 1 insulin-like growth factor receptor.

SUBMITTER: Lawrence CF

PROVIDER: S-EPMC4957034 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor.

Lawrence Callum F CF Margetts Mai B MB Menting John G JG Smith Nicholas A NA Smith Brian J BJ Ward Colin W CW Lawrence Michael C MC

The Journal of biological chemistry 20160608 30

Sets of synthetic peptides that interact with the insulin receptor ectodomain have been discovered by phage display and reported in the literature. These peptides were grouped into three classes termed Site 1, Site 2, and Site 3 based on their mutual competition of binding to the receptor. Further refinement has yielded, in particular, a 36-residue Site 2-Site 1 fusion peptide, S519, that binds the insulin receptor with subnanomolar affinity and exhibits agonist activity in both lipogenesis and ...[more]

PMID: 27281820

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Project description:Male Igfbp2-/- mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/- mice do not have this phenotype but following ovariectomy (OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1 (0.7, 2, and 6?mg·kg-1) and an OVX group receiving parathyroid hormone (PTH) (50?µg·kg-1 per day). The peptides were administered for 8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density (aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2%?±?2.4% (P?<?0.01) compared to control peptide; similar to the increase noted with PTH (5.6%?±?3.0%, P?<?0.01). Similar increases were noted with two lower doses of the peptide (3.8%?±?1.5%, P?<?0.05 for low dose; 3.1%?±?1.6%, P?=?0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and 64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume (BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide (18.9%?±?9.8%, P?<?0.01 and 14.2%?±?7.9%, P?<?0.01 for low dose; 23.7%?±?10.7%, P?<?0.001 and 15.8%?±?6.1%, P?<?0.001 for middle dose; 19.0%?±?6.9%, P?<?0.01 and 16.2%?±?9.7%, P?<?0.001 for high dose) and with PTH (25.8%?±?9.2%, P?<?0.001 and 19.4%?±?8.8%, P?<?0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate (MAR), bone formation rate/bone surface (BFR/BS), number of osteoblasts/bone perimeter (N.ob/B.pm), and decreased osteoclast surface/bone perimeter (Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.

Dataset Information

Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor.

Publications

Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor.

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