A family-based approach reveals the function of residues in the nuclear receptor ligand-binding domain

S. Folkertsma, P. Noort, J. van Durme, H.J. Joosten, E. Bettler, W. Fleuren, L. Oliveira, F. Horn, J. de Vlieg, G. Vriend

Research output: Contribution to journalArticleAcademicpeer-review

29 Citations (Scopus)

Abstract

Literature studies, 3D structure data, and a series of sequence analysis techniques were combined to reveal important residues in the structure and function of the ligand-binding domain of nuclear hormone receptors. A structure-based multiple sequence alignment allowed for the seamless combination of data from many different studies on different receptors into one single functional model. It was recently shown that a combined analysis of sequence entropy and variability can divide residues in five classes; (1) the main function or active site, (2) support for the main function, (3) signal transduction, (4) modulator or ligand binding and (5) the rest. Mutation data extracted from the literature and intermolecular contacts observed in nuclear receptor structures were analyzed in view of this classification and showed that the main function or active site residues of the nuclear receptor ligand-binding domain are involved in cofactor recruitment. Furthermore, the sequence entropy–variability analysis identified the presence of signal transduction residues that are located between the ligand, cofactor and dimer sites, suggesting communication between these regulatory binding sites. Experimental and computational results agreed well for most residues for which mutation data and intermolecular contact data were available. This allows us to predict the role of the residues for which no functional data is available yet. This study illustrates the power of family-based approaches towards the analysis of protein function, and it points out the problems and possibilities presented by the massive amounts of data that are becoming available in the “omics era”. The results shed light on the nuclear receptor family that is involved in processes ranging from cancer to infertility, and that is one of the more important targets in the pharmaceutical industry.
Original languageEnglish
Pages (from-to)321-335
JournalJournal of Molecular Biology
Volume341
Issue number2
DOIs
Publication statusPublished - 2004

Keywords

  • retinoid-x-receptor
  • dependent transcriptional activation
  • pancreatic trypsin-inhibitor
  • protein-coupled receptors
  • crystal-structure
  • structural basis
  • estrogen-receptor
  • androgen receptor
  • hormone-receptors
  • triphosphate conformation

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