2025 Hyper Recent •CC0 1.0 Universal

This work is dedicated to the public domain. No rights reserved.

Access Preprint From Server
May 8th, 2025
Version: 2
Vanderbilt University School of Medicine
biophysics
biorxiv

Structural basis of PPARγ-mediated transcriptional repression by the covalent inverse agonist FX-909

Laughlin, Z. T.Open in Google Scholar•Arifova, L.Open in Google Scholar•Munoz-Tello, P.Open in Google Scholar•Yu, X.Open in Google Scholar•Karadi Giridhar, M. N.Open in Google Scholar•Dong, J.Open in Google Scholar•Harp, J. M.Open in Google Scholar•Zu, D.Open in Google Scholar•Kamenecka, T. M.Open in Google Scholar•Kojetin, D. J.Open in Google Scholar

Hyperactivation of peroxisome proliferator-activated receptor gamma (PPAR{gamma})-mediated transcription promotes tumor growth in urothelial (bladder) cancer, which can be inhibited by pharmacological compounds that repress PPAR{gamma} activity. FX-909 is a covalent PPAR{gamma} inverse agonist currently in phase 1 clinical trials for advanced solid malignancies including muscle-invasive bladder cancer. Here, we compared the mechanism of action of FX-909 to other covalent inverse agonists including T0070907, originally reported more than 20 years ago and misclassified as an antagonist, and two improved analogs, SR33068 and BAY-4931. Functional profiling and NMR studies reveal that FX-909 displays improved corepressor-selective inverse agonism and better stabilizes a transcriptionally repressive PPAR{gamma} LBD conformation compared to T0070907. The crystal structure of PPAR{gamma} LBD cobound to FX-909 and NCoR1 corepressor peptide reveals a repressive conformation shared by other covalent inverse agonists. These findings build on recent studies highlighting the pharmacological significance and clinical relevance of transcriptionally repressive PPAR{gamma} inverse agonists.

Similar Papers

biorxiv
Fri May 09 2025
Structural basis for membrane microdomain formation by a human Stomatin complex
Biological membranes are not just passive barriers-they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 angstrom cryo...
Fu, Z.
•
Stonger, J.
•
Li, S.
biorxiv
Fri May 09 2025
Molecular mechanism of exchange coupling in CLC chloride/proton antiporters
The ubiquitous CLC membrane transporters are unique in their ability to exchange anions for cations. Despite extensive study, there is no mechanistic model that fully explains their 2:1 Cl-/H+ stoichiometric exchange mechanism. Here, we provide such a model. Using differential hydrogen-deuterium exchange mass spectrometry, cryo-EM structure determination, and molecular dynamics simulations, we unc...
Aydin, D.
•
Chien, C.-T.
•
Kreiter, J.
•
Nava, A.
...•
Maduke, M.
biorxiv
Fri May 09 2025
Myelin Mapping in the Human Brain Using an Empirical Extension of the Ridge Regression Theorem
Myelin water fraction (MWF) mapping in the central nervous system is a topic of intense research activity. One framework for this requires parameter estimation from a decaying biexponential signal. However, this is often an ill-posed nonlinear problem resulting in unreliable parameter estimates. For linear least-squares (LLS) problems, the ridge regression theorem (RRT) shows that a Tikhonov regul...
Hampton, G. S.
•
Neff, R.
•
Song, Z.
•
Bouhrara, M.
...•
Spencer, R. G.
biorxiv
Fri May 09 2025
Wide-field fluorescence lifetime imaging of single molecules with a gated single-photon camera
Fluorescence lifetime imaging microscopy (FLIM) is a powerful tool to discriminate fluorescent molecules or probe their nanoscale environment. Traditionally, FLIM uses time-correlated single-photon counting (TCSPC), which is precise but intrinsically low-throughput due to its dependence on point detectors. Although time-gated cameras have demonstrated the potential for high-throughput FLIM in brig...
Ronceray, N.
•
Bennani, S.
•
Mitsioni, M. F.
•
Siegel, N.
...•
Radenovic, A.
biorxiv
Fri May 09 2025
TS2CG as a membrane builder
Molecular dynamics (MD) simulations excel at capturing biological processes at the molecular scale but rely on a well-defined initial structure. As MD simulations now extend to whole-cell-level modeling, new tools are needed to efficiently build initial structures. Here, we introduce TS2CG version 2, designed to construct coarse-grained membrane structures with any desired shape and lateral organi...
Schuhmann, F.
•
Stevens, J. A.
•
Rahmani, N.
•
Lindahl, I.
...•
Pezeshkian, W.
biorxiv
Fri May 09 2025
Generating 3D Models of Carbohydrates with GLYCAM-Web
The carbohydrate 3D structure-prediction tools (builders) at GLYCAM-Web (glycam.org) are widely used for generating experimentally-consistent 3D structures of oligosaccharides suitable for data interpretation, hypothesis generation, simple visualization, and subsequent molecular dynamics (MD) simulation. The graphical user interface (GUI) enables users to create carbohydrate sequences (e.g. DGalpb...
Grant, O. C.
•
Wentworth, D.
•
Holmes, S. G.
•
Kandel, R.
...•
Woods, R. J.
biorxiv
Fri May 09 2025
In silico discovery of compounds targeting NPSL2: a regulatory element in the human oncomiR-1 primary microRNA.
NPSL2 is a stem loop element within the oncomiR-1 polycistronic primary microRNA (miRNA) cluster. NPSL2 is predicted to mediate conformational rearrangements within oncomiR-1 to regulate the biogenesis of certain miRNA elements within the cluster. The regulatory role of NPSL2 makes it a promising target for small molecule ligands, which we explored through structure-based small molecule ligand dis...
Arhin, G.
•
Keane, S. C.
biorxiv
Fri May 09 2025
Single-molecule Mechanostructural Fingerprinting of Nucleic Acid Conformations
Understanding the three-dimensional structure and mechanical response of biomolecules is key to uncovering their molecular mechanisms, particularly in contexts where force plays a regulatory role. Structural methods such as X-ray crystallography, cryo-electron microscopy, and NMR spectroscopy provide high-resolution conformational data, while single-molecule force spectroscopy reveals mechanical p...
Shrestha, P.
•
Shih, W.
•
Wong, W.
biorxiv
Fri May 09 2025
Comparing PAS domain coupled intrinsic dynamics in bHLH PAS domain transcription factor complexes
The basic Helix-Loop-Helix-Per-Arnt-Sim (bHLH-PAS) transcription factors (TFs) are regulators of several critical cellular functions such as circadian rhythm, hypoxia response and neuronal development. These proteins contain tandemly repeated PAS domains that mediate heterodimer formation. While PAS domains adopt a conserved fold, recent studies suggest that their interaction interfaces differ dis...
Sudarsanam, K.
•
Srivastava, A.
•
Tiwari, S. P.
biorxiv
Fri May 09 2025
Micron-scale, liquid-liquid phase separation in ternary lipid membranes containing DPPE
Micron-scale, liquid-liquid phase separation occurs in membranes of living cells, with physiological consequences. To discover which lipids might support phase separation in cell membranes and how lipids might partition between phases, miscibility phase diagrams have been mapped for model membranes. Typically, model membranes are composed of ternary mixtures of a lipid with a high melting temperat...
Goetz, G. J.
•
Naomi, S.
•
Madrigal, A. M.
•
Chang, C. L. A.
...•
Keller, S. L.