title: In silico assessment of interaction of sea anemone toxin APETx2 and acid sensing ion channel 3.
abstract: Acid sensing ion channels (ASICs) are proton-gated cation channels that are expressed throughout the nervous system and have been implicated in mediating sensory perception of noxious stimuli. Amongst the six ASIC isoforms, ASIC1a, 1b, 2a and 3 form proton-gated homomers, which differ in their activation and inactivation kinetics, expression profiles and pharmacological modulation; protons do not gate ASIC2b and ASIC4. As with many other ion channels, structure-function studies of ASICs have been greatly aided by the discovery of some toxins that act in isoform-specific ways. ASIC3 is predominantly expressed by sensory neurons of the peripheral nervous system where it acts to detect acid as a noxious stimulus and thus plays an important role in nociception. ASIC3 is the only ASIC subunit that is inhibited by the sea anemone (Anthopleura elegantissima)-derived toxin APETx2. However, the molecular mechanism by which APETx2 interacts with ASIC3 remains largely unknown. In this study, we made a homology model of ASIC3 and used extensive protein-protein docking to predict for the first time, the probable sites of APETx2 interaction on ASIC3. Additionally, using computational alanine scanning, we also suggest the 'hot-spots' that are likely to be critical for ASIC3-APETx2 interaction.
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. Electronic address: mtur2@cam.ac.uk.
authors.forename: Taufiq
authors.initials: T
authors.lastname: Rahman
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Ewan St John
authors.initials: ES
authors.lastname: Smith
mesh_terms: D062565:Acid Sensing Ion Channels / Q000737:chemistry* / Q000648:ultrastructure*; D000818:Animals; D001665:Binding Sites; D002645:Chickens; D003064:Cnidarian Venoms / Q000737:chemistry*; D003198:Computer Simulation; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats
chemical_list: C501880:APETx2 protein, Anthopleura elegantissima; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D003064:Cnidarian Venoms; D008051:Lipid Bilayers
keywords: APETx2; ASIC3; Homology modelling; Protein–protein docking