A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin.
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 PheB24is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
John G
JG
Menting
Department of Biology, University of Utah, Salt Lake City, Utah, USA.
Joanna
J
Gajewiak
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Christopher A
http://orcid.org/0000-0002-3694-3989
CA
MacRaild
Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA.
Danny Hung-Chieh
DH
Chou
Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA.
Maria M
MM
Disotuar
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
Nicholas A
NA
Smith
Sentia Medical Sciences, San Diego, California, USA.
Charleen
C
Miller
Sentia Medical Sciences, San Diego, California, USA.
Judit
J
Erchegyi
Sentia Medical Sciences, San Diego, California, USA.
Jean E
JE
Rivier
Department of Biology, University of Utah, Salt Lake City, Utah, USA.
Baldomero M
BM
Olivera
Department of Medical Biochemistry, Flinders University, Bedford Park, South Australia, Australia.
Briony E
BE
Forbes
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
Brian J
BJ
Smith
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Raymond S
http://orcid.org/0000-0001-8893-0584
RS
Norton
Department of Biology, University of Utah, Salt Lake City, Utah, USA.|Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Helena
H
Safavi-Hemami
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Michael C
MC
Lawrence
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D052078:Conus Snail / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*; D017279:Selenocysteine / Q000737:chemistry / Q000378:metabolism; D014688:Venoms / Q000737:chemistry / Q000378:metabolism*
D015703:Antigens, CD; D007328:Insulin; D014688:Venoms; D017279:Selenocysteine; C435941:INSR protein, human; D011972:Receptor, Insulin