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Functional probing of the human glucocorticoid receptor steroid-interacting surface by site-directed mutagenesis - Gln-642 plays an important role in steroid recognition and binding
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2000 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 25, p. 19041-19049Article in journal (Refereed) Published
Abstract [en]

To elucidate which amino acids in the glucocorticoid receptor ligand-binding domain might be involved in determining steroid binding specificity by interaction with the D-ring of glucocorticoids, we have performed site-directed mutagenesis of the four amino acids Met-560, Met-639, Gln-642, and Thr-739 based on their proximity to the steroid in a model structure. Mutations of these residues affected steroid binding affinity, specificity, and/or steroid-dependent transactivation. The results indicate that these residues are located in close proximity to the ligand and appear to play a role in steroid recognition and/or transactivating sensitivity, possibly by changes in the steroid-dependent conformational change of this region, resulting in the formation of the AF-2 site. Mutation of Gln-642 resulted in a marked decrease in affinity for steroids containing a 17 alpha-OH group. This effect was alleviated by the presence of a 16 alpha-CH3 group to a varying degree. Thr-739 appears to form a hydrogen bond with the 21-OH group of the steroid, as well as possibly forming hydrophobic interactions with the steroid, Met-EGO and Met-639 appear to form hydrophobic interactions with the D-ring of the steroid, although the nature of these interactions cannot be characterized in more detail at this point.

Place, publisher, year, edition, pages
2000. Vol. 275, no 25, p. 19041-19049
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:sh:diva-15748DOI: 10.1074/jbc.M000228200ISI: 000087815900057PubMedID: 10747884Scopus ID: 2-s2.0-0034705588OAI: oai:DiVA.org:sh-15748DiVA, id: diva2:508071
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved

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Wright, Anthony P H

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CiteExportLink to record
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Citation style
  • apa
  • ieee
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  • vancouver
  • harvard-anglia-ruskin-university
  • Other style
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  • de-DE
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  • en-US
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  • nn-NB
  • sv-SE
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Output format
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