TY - JOUR
T1 - A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin
AU - Menting, John
AU - Gajewiak, Joanna
AU - MacRaild, Christopher
AU - Chou, Danny
AU - Disotuar, Maria
AU - Smith, Nicholas
AU - Miller, Charleen
AU - Erchegyi, Judit
AU - Rivier, Jean
AU - Olivera, Baldomero
AU - Forbes, Briony
AU - Smith, Brian
AU - Norton, Raymond
AU - Safavi-Hemami, Helena
AU - Lawrence, Michael
PY - 2016/10/1
Y1 - 2016/10/1
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.
UR - http://www.nature.com/nsmb/journal/v23/n10/full/nsmb.3292.html
UR - http://www.scopus.com/inward/record.url?scp=84987624996&partnerID=8YFLogxK
U2 - 10.1038/nsmb.3292
DO - 10.1038/nsmb.3292
M3 - Article
VL - 23
SP - 916
EP - 920
JO - NATURE STRUCTURAL & MOLECULAR BIOLOGY
JF - NATURE STRUCTURAL & MOLECULAR BIOLOGY
SN - 1545-9985
IS - 10
ER -