High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1

Access to high-resolution structural data for protein-ligand complexes is a prerequisite for structure-based medicinal chemistry, where the ability to iterate cycles of design-structure-redesign is highly desirable. For proteins refractory to X-ray crystallography, such as integral membrane proteins, enablement of high throughput structure determination by cryoelectron microscopy (cryo-EM) has the potential to be transformational for structure-based design. We have applied such an approach to the lysosomal ion channel transient receptor potential mucolipin 1 (TRPML1) in complex with ten chemically diverse modulators, both agonists and antagonists. The resulting depth of high-resolution structural data generated provides important insights into protein-ligand structure-function relationships, including mechanistic understanding of ligand-induced channel pore opening and closing. Moreover, the knowledge gained has the potential to support iterative design cycles toward improved modulators of this important biological target.

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Publication Details

Journal
Structure
Published
2025-06-17
DOI
https://doi.org/10.1016/j.str.2025.05.014
Citations
2
Primary Topic
Calcium signaling and nucleotide metabolism
Type
article
Field-Weighted Citation Impact
2.24

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article

High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1

Christopher Earl, Rhian S. Holvey, P. Mahajan, Patrick Schöpf et al.
2 citations
Structure
Calcium signaling and nucleotide metabolism
2.24
article

High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1

Christopher Earl, Rhian S. Holvey, P. Mahajan, Patrick Schöpf, Emyr Lloyd‐Evans, Samantha Fisher, Helen Waller‐Evans, Pamela A. Williams, Simon E. Ward, Elena Di Daniel, Stuart Whibley, Paul N. Mortenson, Simone Cowan, Judith Reeks, Scott M. Jackson, Mellissa Clark, Marc O’Reilly, Christopher N. Johnson, Caroline Richardson, D.M. Tams, Carmine M Morgillo
article en
2 citations

Abstract

Access to high-resolution structural data for protein-ligand complexes is a prerequisite for structure-based medicinal chemistry, where the ability to iterate cycles of design-structure-redesign is highly desirable. For proteins refractory to X-ray crystallography, such as integral membrane proteins, enablement of high throughput structure determination by cryoelectron microscopy (cryo-EM) has the potential to be transformational for structure-based design. We have applied such an approach to the lysosomal ion channel transient receptor potential mucolipin 1 (TRPML1) in complex with ten chemically diverse modulators, both agonists and antagonists. The resulting depth of high-resolution structural data generated provides important insights into protein-ligand structure-function relationships, including mechanistic understanding of ligand-induced channel pore opening and closing. Moreover, the knowledge gained has the potential to support iterative design cycles toward improved modulators of this important biological target.

StructureVol. 33(8)
Cardiff University (GB), GW Pharmaceuticals (United Kingdom) (GB)
Astex Pharmaceuticals
Openalex Percentile: Top 13%
Calcium signaling and nucleotide metabolism
2.24
DOIOpen Access PDFOpenAlex
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