Rational modification of estrogen receptor by combination of computational and experimental analysis

Ferrero, Valentina Elisabetta Viviana; Pedotti, Mattia; Chiadò, Alessandro; Simonelli, Luca; Calzolai, Luigi; Varani, Luca; Lettieri, Teresa

doi:10.1371/journal.pone.0102658

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Journal article

Rational modification of estrogen receptor by combination of computational and experimental analysis

Ferrero, Valentina Elisabetta Viviana European Commission - Directorate General - Joint Research Centre, Institute for Environment and Sustainability, Ispra, Varese, Italy
Pedotti, Mattia Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Chiadò, Alessandro Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Simonelli, Luca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Calzolai, Luigi European Commission - Directorate General - Joint Research Centre, Institute for Health and Consumer Protection, Ispra, Varese, Italy
Varani, Luca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Lettieri, Teresa European Commission - Directorate General - Joint Research Centre, Institute for Environment and Sustainability, Ispra, Varese, Italy

30.07.2014

Published in:

Plos one. - 2014, vol. 9, no. 7, p. e102658

English In this manuscript, we modulate the binding properties of estrogen receptor protein by rationally modifying the amino acid composition of its ligand binding domain. By combining sequence alignment and structural analysis of known estrogen receptor- ligand complexes with computational analysis, we were able to predict estrogen receptor mutants with altered binding properties. These predictions were experimentally confirmed by producing single point variants with up to an order of magnitude increased binding affinity towards some estrogen disrupting chemicals and reaching an half maximal inhibitory concentration (IC50) value of 2 nM for the 17α- ethinylestradiol ligand. Due to increased affinity and stability, utilizing such mutated estrogen receptor instead of the wild type as bio-recognition element would be beneficial in an assay or biosensor.

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