Biology subjects

Williams, J. P.

Publications and source records attributed to Williams, J. P..

3 recordsLinked to original sources

bioRxiv2024

Structural Insight into the Function of Human Peptidyl Arginine Deiminase 6

Peptidyl arginine deiminase 6 (PADI6) is vital for early embryonic development in mice and humans, yet its function remains elusive. PADI6 is less conserved than other PADIs and it is currently unknown whether it has a catalytic function. Here we have shown that human PADI6 dimerises like hPADIs 2-4, however, does not bind Ca2+ and is inactive in in vitro assays against standard PADI substrates. By determining the crystal structure of hPADI6, we show that hPADI6 is structured in the absence of Ca2+ where hPADI2 and hPADI4 are not, and the Ca-binding sites are not conserved. Moreover, we show that whilst the key catalytic aspartic acid and histidine residues are structurally conserved, the cysteine is displaced far from the active site centre and the hPADI6 active site pocket appears closed through a unique evolved mechanism in hPADI6, not present in the other PADIs. Taken together, these findings provide insight into how the function of hPADI6 may differ from the other PADIs based on its structure and provides a resource for characterising the damaging effect of clinically significant PADI6 variants.

biochemistry↗

bioRxiv2023

Generative Molecular Design and Experimental Validation of Selective Histamine H1 Inhibitors

Generative molecular design (GMD) is an increasingly popular strategy for drug discovery, using machine learning models to propose, evaluate and optimize chemical structures against a set of target design criteria. We present the ATOM-GMD platform, a scalable multiprocessing framework to optimize many parameters simultaneously over large populations of proposed molecules. ATOM-GMD uses a junction tree variational autoencoder mapping structures to latent vectors, along with a genetic algorithm operating on latent vector elements, to search a diverse molecular space for compounds that meet the design criteria. We used the ATOM-GMD framework in a lead optimization case study to develop potent and selective histamine H1 receptor antagonists. We synthesized 103 of the top scoring compounds and measured their properties experimentally. Six of the tested compounds bind H1 with Kis between 10 and 100 nM and are at least 100-fold selective relative to muscarinic M2 receptors, validating the effectiveness of our GMD approach.

pharmacology and toxicology↗

bioRxiv2020

Pharmacologic manipulation of complement receptor 3 prevents dendritic spine loss and cognitive impairment after acute cranial radiation

Cranial irradiation induces healthy tissue damage that can lead to neurocognitive complications and negatively impact patient quality of life. One type of damage associated with cognitive impairment is loss of neuronal spine density. Based on developmental and disease studies implicating microglia and complement in dendritic spine loss, we hypothesized that irradiation-mediated spine loss is microglial complement receptor 3 (CR3)-dependent, and associated with late-delayed cognitive deficits. Utilizing a model of cranial irradiation (acute, 10 Gy gamma) in C57BL/6 mice we found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits whereas female mice and CR3 knockout mice do not. Moreover, pharmacological blockade of CR3 with leukadherin-1 (LA1) prevented these changes in irradiated male mice. Interestingly, CR3 KO mice showed reduced behavioral task performance suggesting that CR3 is important for normal learning and memory. Improving our understanding of irradiation-mediated mechanisms and sexual dimorphic responses is essential for the identification of novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.

neuroscience↗