6VEQ

Con-Ins G1 in complex with the human insulin microreceptor in turn in complex with Fv 83-7

Summary for 6VEQ

• Entry DOI: 10.2210/pdb6veq/pdb
• Descriptor: Con-Ins G1a A chain, SULFATE ION, Con-Ins G1 B chain, ... (10 entities in total)
• Functional Keywords: toxin
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 148156.97

Authors

Menting, J.G.,Chou, D.H.-C.,Lawrence, M.C.,Xiong, X. (deposition date: 2020-01-02, release date: 2020-06-03, Last modification date: 2023-11-15)

Primary citation

Xiong, X.,Menting, J.G.,Disotuar, M.M.,Smith, N.A.,Delaine, C.A.,Ghabash, G.,Agrawal, R.,Wang, X.,He, X.,Fisher, S.J.,MacRaild, C.A.,Norton, R.S.,Gajewiak, J.,Forbes, B.E.,Smith, B.J.,Safavi-Hemami, H.,Olivera, B.,Lawrence, M.C.,Chou, D.H.
A structurally minimized yet fully active insulin based on cone-snail venom insulin principles.
Nat.Struct.Mol.Biol., 27:615-624, 2020

PubMed Abstract: Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.

PubMed: 32483339
DOI: 10.1038/s41594-020-0430-8

Experimental method

X-RAY DIFFRACTION (3.25 Å)