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The insulin receptor is a membrane protein responsible for the regulation of nutrient balance; and therefore, it is an attractive target in the treatment of diabetes and metabolic syndrome. Pharmacology of the insulin receptor involves two distinct mechanisms: (1) activation of the receptor by insulin mimetics that bind in the extracellular domain and (2) inhibition of the receptor TK enzymatic activity in the cytoplasmic domain. While a complete structural picture of the full‐length receptor comprising the entire sequence covering extracellular, transmembrane, juxtamembrane and cytoplasmic domains is still elusive, recent progress through cryoelectron microscopy has made it possible to describe the initial insulin ligand binding events at atomistic detail. We utilize this opportunity to obtain structural insights into the pharmacology of the insulin receptor. To this end, we conducted a comprehensive docking study of known ligands to the new structures of the receptor. Through this approach, we provide an in‐depth, structure‐based review of human insulin receptor pharmacology in light of the new structures. LINKED ARTICLESThis article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visithttp://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc
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Structural basis of AMPA receptor inhibition by trans ‐4‐butylcyclohexane carboxylic acid
Background and PurposeAMPA receptors, which shape excitatory postsynaptic currents and are directly involved in overactivation of synaptic function during seizures, represent a well‐accepted target for anti‐epileptic drugs. Trans‐4‐butylcyclohexane carboxylic acid (4‐BCCA) has emerged as a new promising anti‐epileptic drug in several in vitro and in vivo seizure models, but the mechanism of its action remained unknown. The purpose of this study is to characterize structure and dynamics of 4‐BCCA interaction with AMPA receptors. Experimental ApproachWe studied the molecular mechanism of AMPA receptor inhibition by 4‐BCCA using a combination of X‐ray crystallography, mutagenesis, electrophysiological assays, and molecular dynamics simulations. Key ResultsWe identified 4‐BCCA binding sites in the transmembrane domain (TMD) of AMPA receptor, at the lateral portals formed by transmembrane segments M1–M4. At this binding site, 4‐BCCA is very dynamic, assumes multiple poses, and can enter the ion channel pore. Conclusion and Implications4‐BCCA represents a low‐affinity inhibitor of AMPA receptors that acts at the TMD sites distinct from non‐competitive inhibitors, such as the anti‐epileptic drug perampanel and the ion channel blockers. Further studies might examine the possibsility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas. LINKED ARTICLESThis article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visithttp://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc
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- Award ID(s):
- 1818086
- PAR ID:
- 10445886
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- British Journal of Pharmacology
- Volume:
- 179
- Issue:
- 14
- ISSN:
- 0007-1188
- Page Range / eLocation ID:
- p. 3628-3644
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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