7N43

Alpha-conotoxin OmIA with unusual pharmacological properties at alpha7 nicotinic receptors

Summary for 7N43

• Entry DOI: 10.2210/pdb7n43/pdb
• Descriptor: Acetylcholine-binding protein, Alpha-conotoxin OmIA (3 entities in total)
• Functional Keywords: alpha-conotoxin, acetylcholine-binding protein, choline-binding protein
• Biological source: Lymnaea stagnalis (Great pond snail); More
• Total number of polymer chains: 10
• Total formula weight: 127942.49

Authors

Ho, T.N.T.,Abraham, N.,Lewis, R.J. (deposition date: 2021-06-03, release date: 2021-12-01, Last modification date: 2024-11-20)

Primary citation

Ho, T.N.T.,Abraham, N.,Lewis, R.J.
Unique Pharmacological Properties of alpha-Conotoxin OmIA at alpha 7 nAChRs.
Front Pharmacol, 12:803397-803397, 2021

PubMed Abstract: OmIA, isolated from venom, is a potent antagonist at α7 nAChRs. We determined the co-crystal structure of OmIA with acetylcholine binding protein (-AChBP) that identified His5, Val10 and Asn11 as key determinants for the high potency of OmIA at α7 nAChRs. Remarkably, despite a competitive binding mode observed in the co-crystal structure, OmIA and analogues displayed functional insurmountable antagonism at α7 and α3β4 nAChRs, except OmIA analogues having long side chain at position 10 ([V10Q]OmIA and [V10L]OmIA), which were partial insurmountable antagonist at α7 nAChRs in the presence of type II positive allosteric modulators (PAMs). A "two-state, two-step" model was used to explain these observations, with [V10Q]OmIA and [V10L]OmIA co-existing in a fast reversible/surmountable as well as a tight binding/insurmountable state. OmIA and analogues also showed biphasic-inhibition at α7 nAChRs in the presence of PNU120596, with a preference for the high-affinity binding site following prolonged exposure. The molecular basis of binding and complex pharmacological profile of OmIA at α7 nAChRs presented in here expands on the potential of α-conotoxins to probe the pharmacological properties of nAChRs and may help guide the development novel α7 modulators.

PubMed: 34955864
DOI: 10.3389/fphar.2021.803397

Experimental method

X-RAY DIFFRACTION (2.47 Å)