An automated Template Search Tool for Homology Modelling of Family/class A GPCRs


GPCR-SSFE: A comprehensive database of G-protein-coupled receptor template predictions and homology models.
CL Worth, A Kreuchwig, G Kleinau and G Krause. 2011. BMC Bioinformatics 2011, 12:185.
Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.

Their tool allows users to search suitable template crystal structures obtained before November 2010 (PDB:1U19, 2Z73, 2VT4, 2RH1 and 3EML). I am hoping that they are updating the site with newly obtained crystal structures, though that might involve a quite amount of work…. The site is visually well-presented and user friendly.


Summary

GPCR-Sequence Structure Feature Extractor (SSFE) dataset contains 5025 sequences of Family/class A GPCRs, stored in the GPCRDB by October 2009. As for receptors that are not included in the database, they accept sequence submission by users for analysis and homology model building (see Running GPCR-SSFE section below).

They used HMMER2 (HMMER3 available now by the way) to generate a profile hidden Markov model (HMM) from a multiple sequence alignment (MSA) of the five templates and 54 Family/class A GPCRs.

The most suitable template is searched for each transmembrane domain (TM) and helix 8 (H8), as described in their previous paper (Worth, Kleinau & Krause 2009).

Homology models of query GPCRs were generated by Modeller9v7 .

Result page displays:
1) Templates used;
2) MSA for TMs and H8;
3) MSA of the profile HMM GPCR sequences and the query;
4) The HMMER2 e-value for the full-length MSA;
5) The template suggestions for TMs and H8;
6) Sequence similarity score between suggested and the query;
7) The rationale for the suggested templates;
8) A Jmol applet showing the homology model of the query;
9) Sequences of intracellular and extracellular loops;
10) Links to other databases (UniProt, GPCRDB, Human-gpDB and GPCR-OKB when relevant).

Also Ramachandran plot (by PROCHECK) of each model is provided for stereochemical quality check.

Running GPCR-SSFE:
For orphans not on their database, users may submit query sequences in FASTA format via “Run SSFE” page. The tool asks users to submit a Modeller license key, which is obtainable by members of academic institutions freely at the Modeller website; the user will also be asked to submit an e-mail address to which a web-link is sent; the web-link is stored for 7 days - according to the instruction give by the above paper (Worth et al. 2011).

The GPCR-SSFE Database


Reference
Worth CL, Kleinau G & Krause G. 2009. Comparative sequence and structural analyses of G-protein-coupled receptor crystal structures and implications for molecular models. PLoS One. 4:e7011.