Designed Spiroketal Protein Modulation

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Abstract: 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.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: Designed Spiroketal Protein Modulation ; volume:56 ; number:20 ; year:2017 ; pages:5480-5484 ; extent:5
Angewandte Chemie / International edition. International edition ; 56, Heft 20 (2017), 5480-5484 (gesamt 5)

Creator: Scheepstra, Marcel
Andrei, Sebastian A.
Unver, M. Yagiz
Hirsch, Anna K. H.
Leysen, Seppe
Ottmann, Christian
Brunsveld, Luc
Milroy, Lech‐Gustav

DOI: 10.1002/anie.201612504

URN: urn:nbn:de:101:1-2022091605482652581761

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:40 AM CEST

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Associated

Scheepstra, Marcel
Andrei, Sebastian A.
Unver, M. Yagiz
Hirsch, Anna K. H.
Leysen, Seppe
Ottmann, Christian
Brunsveld, Luc
Milroy, Lech‐Gustav

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