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Designed Spiroketal Protein Modulation
Author(s) -
Scheepstra Marcel,
Andrei Sebastian A.,
Unver M. Yagiz,
Hirsch Anna K. H.,
Leysen Seppe,
Ottmann Christian,
Brunsveld Luc,
Milroy LechGustav
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201612504
Subject(s) - allosteric regulation , activator (genetics) , chemistry , ternary complex , nuclear receptor , partial agonist , stereochemistry , agonist , rational design , drug discovery , docking (animal) , receptor , combinatorial chemistry , biochemistry , enzyme , biology , transcription factor , medicine , genetics , nursing , gene
Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co‐activator recruitment. We solved the crystal structure of the spiroketal–hRXRα–TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co‐crystal structure, the first of a designed spiroketal–protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.