5LYQ

Crystal structure of the Retinoic Acid Receptor alpha in complex with a synthetic spiroketal agonist and a fragment of the TIF2 co-activator.

Summary for 5LYQ

• Entry DOI: 10.2210/pdb5lyq/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP, (2~{R})-6,6,9,9-tetramethylspiro[3,4,7,8-tetrahydrobenzo[g]chromene-2,2'-3,4-dihydrochromene]-6'-carboxylic acid, ... (4 entities in total)
• Functional Keywords: nuclear receptor, rxr, spiroketal, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P19793
• Total number of polymer chains: 2
• Total formula weight: 28842.42

Authors

Andrei, S.A.,Ottmann, C. (deposition date: 2016-09-28, release date: 2017-04-26, Last modification date: 2024-01-17)

Primary citation

Scheepstra, M.,Andrei, S.A.,Unver, M.Y.,Hirsch, A.K.H.,Leysen, S.,Ottmann, C.,Brunsveld, L.,Milroy, L.G.
Designed Spiroketal Protein Modulation.
Angew. Chem. Int. Ed. Engl., 56:5480-5484, 2017

PubMed 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.

PubMed: 28407400
DOI: 10.1002/anie.201612504

Experimental method

X-RAY DIFFRACTION (2.17 Å)