NAChRDB: A Web Resource of Structure-Function Annotations to Unravel the Allostery of Nicotinic Acetylcholine Receptors

Abstract

Nicotinic acetylcholine receptors (nAChRs) comprise a large and ancient family of allosteric ion channels mediating synaptic transmission. The vast knowledge about nAChRs has become difficult to navigate. NAChRDB is a web-accessible resource of curated residue-level functional annotations of neuromuscular nAChRs. Interactive three-dimensional (3D) visualization and sequence alignment give further context to this rich and growing collection of experimental observations and computational predictions. NAChRDB is freely available at https://crocodile.ncbr.muni.cz/Apps/NAChRDB/, with interactive tutorials and regular updates to the content and web interface. No installation or user registration is required. NAChRDB is accessible through any modern internet browser on desktops and mobile devices. By providing immediate and systematic access to practical knowledge gained through decades of research, NAChRDB represents a powerful educational tool and helps guide discovery by revealing gaps in current knowledge and aiding the interpretation of results of molecular and structural biology experiments or computational studies.

Figure 1

Flowchart of the literature scanning process. Functional annotations were collected from a semisystematic literature review of Medline through PubMed. First, we searched PubMed for articles describing the functional role of neuromuscular nicotinic acetylcholine receptor (nAChR) amino acid residues. Next, we briefly reviewed the titles and abstracts and excluded unsuitable papers. We then reviewed the full text of the remaining articles and retained only relevant papers that covered studies using subunit types, chain IDs, and residue numbering corresponding to the canonical sequences of nAChR subunits.

Figure 2

Recent screenshot of the NAChRDB workspace. The NAChRDB user interface is organized into tabs. The “Workspace” tab (A, active in the screenshot), which serves for conducting searches and examining models and sequences, contains: (1) a 3D viewer widget providing interactive visualization of nAChR 3D models, complete with (2) direct reporting of annotation records for a selected residue and (3) settings for adjusting the 3D representation (collapsed in the screenshot); (4) a search section providing extensive, PubMed-like search functionality for querying structure, function, and literature-related fields; and (5) a sequence alignment viewer is available for relevant comparisons and also allows listing any annotation records available for a selected residue. The “Examine results” tab (B) summarizes the search results in an interactive table that also allows users to filter data sets and perform additional operations. All results can be downloaded in the csv and json format for further processing. The “Contribute” tab (C) allows users to report annotations. A dedicated help section (D) provides access to key information about nAChRs and NAChRDB, together with interactive tutorials and case studies, as well as a user experience survey.

Figure 3

Case studies illustrating the usefulness of NAChRDB as a unified resource for structure–function annotations of neuromuscular nAChRs. Color coding on the 3D model: (A) yellow—residues discussed only in reports from nonhuman studies; (B) blue—residues predicted to affect the function based on channel-lining calculation (Pravda et al. and current study; left panel) or charge-profile analysis (Ionescu et al. and current study; right panel); green—residues predicted to affect the channel function based on channel-lining calculation (Pravda et al. and current study; left panel) or charge-profile analysis (Ionescu et al. and current study; right panel), but which were also studied elsewhere and reported to play a role (subset of blue); and (C) purple—residues for which some studies suggested an important role, whereas other studies suggested no important role. The 3D model of Torpedo marmorata neuromuscular nAChR (PDB ID: 2BG9) was used for graphical representation in all panels.