Nucleic Acids Research, 2003, Vol. 31, No. 1 331-333
© 2003 Oxford University Press
NRMD: Nuclear Receptor Mutation Database
CMBI, University of Nijmegen, Nijmegen, The Netherlands 1 Department of Cellular and Molecular Pharmacology, UCSF, Box 0450, San Francisco, CA 94143-0450, USA
*To whom correspondence should be addressed. Email: vriend{at}cmbi.kun.nl
Received August 19, 2002; Revised and Accepted October 30, 2002
ABSTRACT
The NRMD is a database for nuclear receptor mutation information. It includes mutation information from SWISS-PROT/TrEMBL, several web-based mutation data resources, and data extracted from the literature in a fully automatic manner. Because it is also possible to add mutations manually, a hundred mutations were added for completeness. At present, the NRMD contains information about 893 mutations in 54 nuclear receptors. A common numbering scheme for all nuclear receptors eases the use of the information for many kinds of studies. The NRMD is freely available to academia and industry as a stand-alone version at: www.receptors.org/NR/.
INTRODUCTION
Nuclear receptors (NRs) play a crucial role in the regulation of gene expression, and are thus an important target for the pharmaceutical industry. NRs consist of multiple domains, among which are a DNA-binding domain and a ligand-binding domain (LBD). The NRMD deals mainly with mutations in the LBD.
Binding of hormones such as testosterone, vitamin D3 or retinoic acid to LBDs leads to dimerization and binding of a co-activator or co-repressor, which in turn leads to transcription regulation. A good understanding of this process at the molecular level is important for the pharmaceutical industry. Mutation studies are an important source of data on the role of individual amino acids, and together with structural data about amino acid–ligand interactions, they play a central role in the rational drug design process.
The function of residues in NRs is mainly determined by their location (Folkertsma et al. in preparation; www.receptors.org/NR/struct/alignmt.html). Therefore, a mutation of a residue at a certain position in one receptor is likely to have a similar effect as the mutation of a different residue at the equivalent position in another receptor. The structural equivalence of residue positions can thus be used to transfer information about mutations in one NR to all other NRs. To aid this transfer of information, we introduced a common structure-based numbering scheme for all NRs.
The NRMD is part of a larger project aimed at the design of Molecular Class Specific Information Systems (MCSISs). Well-known examples of MCSISs are the GPCRDB (www.gpcr.org) (1) and the NucleaRDB (www.receptors.org/NR/) (2). The NRMD currently exists as a stand-alone mutation information resource, but full integration in the NucleaRDB is well underway.
RESULTS
Several mutation information resources are available. SWISS-PROT/TrEMBL (3) contain sequences of about 1300 NRs, and from their annotation, information about 359 variants can easily be extracted. A fully automatic search of OMIM (4) for NR mutations is difficult, but a human-aided computer script could extract 156 mutants from this resource. The Vitamin D receptor (VDR) pages contain well-documented information about vitamin D receptors. The Photoreceptor cell-specific Nuclear Receptor pages (PNR) (5) specialize in the photoreceptor cell-specific nuclear receptor, and the Glucocorticoid Receptor Resource (GRR) (6) contains a lot of information about glucocorticoid receptors. The NucleaRDB provides point mutation data (www.receptors.org/NR/mutation/) automatically extracted from the literature (Horn and Cohen, in preparation). Using pattern matching, the method ‘MuteXt’ retrieves articles and extracts point mutations, which are then validated by plausibility filters. These filters use the sequence data and the in-text distances between receptor names, organism types and mutants. The preliminary evaluation of MuteXt yields a recall of 85%, a precision of 90% and a coverage of 70%. The recall is the percentage of point mutations that are correctly extracted [true positives/(true positives+false negatives)], the precision is the percentage of validated point mutations that are correct [true positives/(true positives+false positives)] and the coverage is the percentage of relevant point mutations that the system extracted (true and false positives/point mutations present in the documents). Table 1 summarizes the resources at the basis for the NRMD, and Table 2 summarizes the information stored per mutation.
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A WWW-based form gives access to a system that allows the user to query the information. Figure 1 shows the layout of this form.
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In summary, the NRMD combines NR mutation information from all known sources. Most data collection is fully automatic for the web-based resources so that updates will automatically lead to an update of the NRMD. Moreover, mutation information from the literature continues to be added manually. To ensure high quality data, mutations are only accepted if they are made in a sequence available from SWISS-PROT or TrEMBL, and if the mutation is annotated correctly (i.e. residue number, residue type, sequence name, accession code, etc. all are the same in SWISS-PROT or TrEMBL and in the mutation information resource). Additional information about the NRMD is available at: www.receptors.org/NR/.
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