Congratulations to the @mutexazjy.bsky.social lab on receiving an NSF Award for their development of an enzymology database as an infrastructure!
Vanderbilt Center for Structural Biology
@vanderbiltcsb.bsky.social
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Vanderbilt Center for Structural Biology - Research dedicated to determining the 3D structure of biological macromolecules at or near atomic resolution. www.vanderbilt.edu/csb
![a AF-2 surface differences between PPARγ LBD in the transcriptionally active conformation bound to agonist rosiglitazone and TRAP220/MED1 coactivator peptide (PDB 6ONJ) and repressive conformation bound to inverse agonist T0070907 and NCoR1 corepressor peptide (PDB 6ONI) peptides. Coactivator and corepressor peptides are shown in green and pink, respectively. Helical structural elements are noted (h3, h4, h5, h12) and residue names are called out. b Pi stacking between the polar T0070907 pyridyl group and three residues (His323, His449, and Tyr473) and a bridging water molecule form in the transcriptionally repressive conformation (PDB 6ONI). c Compound scaffold of parent molecules containing polar pyridyl (T0070907) and hydrophobic phenyl (GW9662) groups in relation to the polar benzamide group in ZINC5672437. d TR-FRET NCoR1 corepressor biochemical interaction assay (n = 3 biological replicates; mean ± s.e.m.). e Cellular luciferase transcriptional reporter assay in HEK293T cells treated with 10 µM compound (n = 4 biological replicates; mean ± s.e.m.). f Crystal structures showing the compound flipped binding modes in transcriptionally active vs. repressive conformations when bound to GW9662 (PDB 3B0R and 8FHE), T0070907 (PDB 6C1I and 6ONI), or ZINC5672437 (PDB 8FHF and 8FHE). g ZINC5672437 pi-stacking interaction in the repressive state (PDB 8FHE) where the benzamide replaces the bridging water in the T0070907-bound structure (PDB 6ONI). h 2D [1H,15N]-TROSY-HSQC NMR focused on Gly399 of 15N-labeled PPARγ LBD bound to GW9662, T0070907, or ZINC5672437 in the absence (solid lines) or presence (dashed lines) of NCoR1 corepressor peptide. i Data-informed design hypothesis to improve PPARγ inverse agonism.](https://cdn.bsky.app/img/feed_thumbnail/plain/did:plc:rz32aq4sjgd64welwsucyb5e/bafkreiay5lzbse3a54rbelrzuyof5i2xq7nh6nob2ujztdp5xplunywni4)
