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1. Quantification of ligand and mutation-induced bias in EGFR phosphorylation in direct response to ligand binding

   https://doi.org/10.1038/s41467-023-42926-8  

   Wirth, Daniel; Özdemir, Ece; Hristova, Kalina (December 2023, Nature Communications)

   Signaling bias is the ability of a receptor to differentially activate downstream signaling pathways in response to different ligands. Bias investigations have been hindered by inconsistent results in different cellular contexts. Here we introduce a methodology to identify and quantify bias in signal transduction across the plasma membrane without contributions from feedback loops and system bias. We apply the methodology to quantify phosphorylation efficiencies and determine absolute bias coefficients. We show that the signaling of epidermal growth factor receptor (EGFR) to EGF and TGFα is biased towards Y1068 and against Y1173 phosphorylation, but has no bias for epiregulin. We further show that the L834R mutation found in non-small-cell lung cancer induces signaling bias as it switches the preferences to Y1173 phosphorylation. The knowledge gained here challenges the current understanding of EGFR signaling in health and disease and opens avenues for the exploration of biased inhibitors as anti-cancer therapies. 

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2. Luminescent Arylalkynyltitanocenes: Effect of Modifying the Electron Density at the Arylalkyne Ligand, or Adding Steric Bulk or Constraint to the Cyclopentadienyl Ligand

   https://doi.org/10.3390/cryst15080745  

   Barker, Matilda; Walter, Samantha C; McCallum, Elizabeth A; Golden, River S; Zimmerman, John H; McCarthy, Jackson S; McMillen, Colin D; Wagenknecht, Paul S (August 2025, Crystals)

   Photocatalysis using complexes of d0 metals with ligand-to-metal charge-transfer (LMCT) excited states is an active area of research. Because titanium is the second most abundant transition metal in the earth’s crust, d0 complexes of TiIV are an appropriate target for this research. Recently, our group has demonstrated that the arylethynyltitanocene Cp2Ti(C2Ph)2CuBr is not emissive in room-temperature fluid solution, whereas the corresponding Cp* complex, Cp*2Ti(C2Ph)2CuBr, is emissive. The Cp* ligand is hypothesized to provide steric constraint that inhibits excited-state structural rearrangement. However, modifying the structure also changes the orbital character of the excited state. To investigate the impact of the excited-state orbital character on the photophysics, herein we characterize complexes similar to Cp*2Ti(C2Ph)2CuBr—but one with a more electron-rich arylethynyl ligand, ethynyldimethylaniline (C2DMA), and one with a more electron-poor arylethynyl ligand, ethynyl-α,α,α-trifluorotoluene. We have also prepared complexes with the C2DMA ligand but with different Cp ligands that adjust the steric bulk and constraint around the Ti, by replacing the Cp* ligands with either indenyl ligands or an ansa-cyclopentadienyl ligand where the two Cp ligands are bridged by a dimethylsilylene. All four target complexes have been characterized crystallographically and structure activity relationships are highlighted. 

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3. Ligand-binding pockets in RNA and where to find them

   https://doi.org/10.1073/pnas.2422346122  

   Veenbaas, Seth D; Koehn, Jordan T; Irving, Patrick S; Lama, Nicole N; Weeks, Kevin M (April 2025, Proceedings of the National Academy of Sciences)

   RNAs are critical regulators of gene expression, and their functions are often mediated by complex secondary and tertiary structures. Structured regions in RNA can selectively interact with small molecules—via well-defined ligand-binding pockets—to modulate the regulatory repertoire of an RNA. The broad potential to modulate biological function intentionally via RNA–ligand interactions remains unrealized, however, due to challenges in identifying compact RNA motifs with the ability to bind ligands with good physicochemical properties (often termed drug-like). Here, we devisefpocketR, a computational strategy that accurately detects pockets capable of binding drug-like ligands in RNA structures. Remarkably few, roughly 50, of such pockets have ever been visualized. We experimentally confirmed the ligandability of novel pockets detected withfpocketRusing a fragment-based approach introduced here, Frag-MaP, that detects ligand-binding sites in cells. Analysis of pockets detected byfpocketRand validated by Frag-MaP reveals dozens of sites able to bind drug-like ligands, supports a model for RNA secondary structural motifs able to bind quality ligands, and creates a broad framework for understanding the RNA ligand-ome. 

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4. Quantifying the Interdependence of Metal–Ligand Covalency and Bond Distance Using Ligand K‐edge XAS

   https://doi.org/10.1002/anie.201905635  

   Lee, Kyounghoon; Blake, Anastasia V.; Donahue, Courtney M.; Spielvogel, Kyle D.; Bellott, Brian J.; Daly, Scott R. (August 2019, Angewandte Chemie International Edition)

   Abstract Bond distance is a common structural metric used to assess changes in metal–ligand bonds, but it is not clear how sensitive changes in bond distances are with respect to changes in metal–ligand covalency. Here we report ligand K‐edge XAS studies on Ni and Pd complexes containing different phosphorus(III) ligands. Despite the large number of electronic and structural permutations, P K‐edge pre‐edge peak intensities reveal a remarkable correlation that spectroscopically quantifies the linear interdependence of covalent M−P σ bonding and bond distance. Cl K‐edge studies conducted on many of the same Ni and Pd compounds revealed a poor correlation between M−Cl bond distance and covalency, but a strong correlation was established by analyzing Cl K‐edge data for Ti complexes with a wider range of Ti−Cl bond distances. Together these results establish a quantitative framework to begin making more accurate assessments of metal–ligand covalency using bond distances from readily‐available crystallographic data. 

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5. Structural Changes to the Gd‐DTPA Complex at Varying Ligand Protonation State

   https://doi.org/10.1002/ejic.202300507  

   Summers, Thomas_J; O'Brien, Ravi_D; Sobrinho, Josiane_A; de_Bettencourt‐Dias, Ana; Cantu, David_C (November 2023, European Journal of Inorganic Chemistry)

   Abstract Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent whose complex with the Gd³⁺ion is used in medical imaging. DTPA is also used in lanthanide‐actinide separation processes. As protonation of the DTPA ligand can facilitate dissociation of the Gd³⁺ion from the Gd‐DTPA complex, this work investigates the coordination structures of the aqueous Gd³⁺ion and its environment when chelated by DTPA in eight different DTPA protonation states. Both classical and ab initio molecular dynamics (MD) simulations are conducted to model the solvated complexes. Extended X‐ray absorption fine structure (EXAFS) measurements of the Gd³⁺aqua ion, and the Gd‐DTPA complex at pH 1 and 11, are compared to EXAFS spectra predicted from the MD simulations to verify the accuracy of the MD structures. The findings of this work provide atomic‐level details into the fluctuating Gd‐DTPA complex environment as the DTPA ligand gradually detaches from the Gd³⁺ion with increased protonation. 

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