Biology subjects

Holton, J. M.

Publications and source records attributed to Holton, J. M..

2 recordsLinked to original sources

bioRxiv2018

Challenge data set for macromolecular multi-microcrystallography

A synthetic data set demonstrating a particularly challenging case of indexing ambiguity in the context of radiation damage was generated in order to serve as a standard benchmark and reference point for the ongoing development of new methods and new approaches to solving this problem. Of the 100 short wedges of data only the first 71 are currently necessary to solve the structure by \"cheating\", or using the correct reference structure as a guide. The total wall-clock time and number of wedges required to solve the structure without cheating is proposed as a metric for the efficacy and efficiency of a given multi-crystal automation pipeline.\n\nSynopsisA synthetic dataset demonstrating the challenges of combining multiple data sets with indexing ambiguity in the context of heavy radiation damage in multi-crystal macromolecular crystallography was generated and described, and the problems encountered using contemporary data processing programs were summarized.

biophysics↗

bioRxiv2018

Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite

Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinsons disease, a neurological disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks several classic regulatory elements of nuclear receptor function, including the canonical ligand-binding pocket. Here we report that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to and modulates the activity of Nurr1. Using biophysical assays and x-ray crystallography we show that DHI binds to the ligand binding domain within a non-canonical pocket, forming a covalent adduct with Cys566. In cultured cells and zebrafish, DHI stimulates Nurr1 activity, including the transcription of target genes underlying dopamine homeostasis. These findings suggest avenues for developing synthetic Nurr1 ligands to ameliorate the symptoms and progression of Parkinsons disease.

biophysics↗