8HHQ

Covalent bond formation between cysteine of PPARg-LBD and iodoacetic acid

Summary for 8HHQ

• Entry DOI: 10.2210/pdb8hhq/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, GLYCOLIC ACID (3 entities in total)
• Functional Keywords: pparg-lbd, iodoacetic acid, cysteine, covalent modifier, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 63051.14

Authors

Kojima, H.,Itoh, T. (deposition date: 2022-11-16, release date: 2023-09-20, Last modification date: 2023-11-15)

Primary citation

Kojima, H.,Yanagi, R.,Higuchi, E.,Yoshizawa, M.,Shimodaira, T.,Kumagai, M.,Kyoya, T.,Sekine, M.,Egawa, D.,Ohashi, N.,Ishida, H.,Yamamoto, K.,Itoh, T.
Covalent Modifier Discovery Using Hydrogen/Deuterium Exchange-Mass Spectrometry.
J.Med.Chem., 66:4827-4839, 2023

PubMed Abstract: Covalent ligands are generally filtered out of chemical libraries used for high-throughput screening, because electrophilic functional groups are considered to be pan-assay interference compounds (PAINS). Therefore, screening strategies that can distinguish true covalent ligands from PAINS are required. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) is a powerful tool for evaluating protein stability. Here, we report a covalent modifier screening approach using HDX-MS. In this study, HDX-MS was used to classify peroxisome proliferator-activated receptor γ (PPARγ) and vitamin D receptor ligands. HDX-MS could discriminate the strength of ligand-protein interactions. Our HDX-MS screening method identified LT175 and nTZDpa, which can bind concurrently to the PPARγ ligand-binding domain (PPARγ-LBD) with synergistic activation. Furthermore, iodoacetic acid was identified as a novel covalent modifier that stabilizes the PPARγ-LBD.

PubMed: 36994595
DOI: 10.1021/acs.jmedchem.2c01986

Experimental method

X-RAY DIFFRACTION (2.4 Å)