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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 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, nr 25, s. 19041-19049Artikel i tidskrift (Refereegranskat) 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.

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2000. Vol. 275, nr 25, s. 19041-19049
Nationell ämneskategori
Biokemi och molekylärbiologi
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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
Tillgänglig från: 2012-03-07 Skapad: 2012-03-07 Senast uppdaterad: 2017-12-07Bibliografiskt granskad

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Wright, Anthony P H

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