A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin

John G. Menting, Joanna Gajewiak, Christopher MacRaild, Danny Hung Chieh Chou, Maria M. Disotuar, Nicholas A Smith, Charleen Miller, Judit Erchegyi, Jean E. Rivier, Baldomero M. Olivera, Briony E. Forbes, Brian J Smith, Raymond Norton, Helena Safavi-Hemami, Michael C. Lawrence

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue Phe B24 is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.

Original languageEnglish
Pages (from-to)916-920
Number of pages5
JournalNature Structural and Molecular Biology
Volume23
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

Cite this

Menting, J. G., Gajewiak, J., MacRaild, C., Chou, D. H. C., Disotuar, M. M., Smith, N. A., ... Lawrence, M. C. (2016). A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. Nature Structural and Molecular Biology, 23(10), 916-920. https://doi.org/10.1038/nsmb.3292
Menting, John G. ; Gajewiak, Joanna ; MacRaild, Christopher ; Chou, Danny Hung Chieh ; Disotuar, Maria M. ; Smith, Nicholas A ; Miller, Charleen ; Erchegyi, Judit ; Rivier, Jean E. ; Olivera, Baldomero M. ; Forbes, Briony E. ; Smith, Brian J ; Norton, Raymond ; Safavi-Hemami, Helena ; Lawrence, Michael C. / A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. In: Nature Structural and Molecular Biology. 2016 ; Vol. 23, No. 10. pp. 916-920.
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abstract = "Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue Phe B24 is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.",
author = "Menting, {John G.} and Joanna Gajewiak and Christopher MacRaild and Chou, {Danny Hung Chieh} and Disotuar, {Maria M.} and Smith, {Nicholas A} and Charleen Miller and Judit Erchegyi and Rivier, {Jean E.} and Olivera, {Baldomero M.} and Forbes, {Briony E.} and Smith, {Brian J} and Raymond Norton and Helena Safavi-Hemami and Lawrence, {Michael C.}",
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Menting, JG, Gajewiak, J, MacRaild, C, Chou, DHC, Disotuar, MM, Smith, NA, Miller, C, Erchegyi, J, Rivier, JE, Olivera, BM, Forbes, BE, Smith, BJ, Norton, R, Safavi-Hemami, H & Lawrence, MC 2016, 'A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin' Nature Structural and Molecular Biology, vol. 23, no. 10, pp. 916-920. https://doi.org/10.1038/nsmb.3292

A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. / Menting, John G.; Gajewiak, Joanna; MacRaild, Christopher; Chou, Danny Hung Chieh; Disotuar, Maria M.; Smith, Nicholas A; Miller, Charleen; Erchegyi, Judit; Rivier, Jean E.; Olivera, Baldomero M.; Forbes, Briony E.; Smith, Brian J; Norton, Raymond; Safavi-Hemami, Helena; Lawrence, Michael C.

In: Nature Structural and Molecular Biology, Vol. 23, No. 10, 01.10.2016, p. 916-920.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Gajewiak, Joanna

AU - MacRaild, Christopher

AU - Chou, Danny Hung Chieh

AU - Disotuar, Maria M.

AU - Smith, Nicholas A

AU - Miller, Charleen

AU - Erchegyi, Judit

AU - Rivier, Jean E.

AU - Olivera, Baldomero M.

AU - Forbes, Briony E.

AU - Smith, Brian J

AU - Norton, Raymond

AU - Safavi-Hemami, Helena

AU - Lawrence, Michael C.

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N2 - Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue Phe B24 is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.

AB - Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue Phe B24 is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.

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