Reeks, Judith, Mahajan, Pravin, Clark, Mellissa, Cowan, Suzanna R., Di Daniel, Elena, Earl, Christopher P., Fisher, Samantha, Holvey, Rhian S., Jackson, Scott M., Lloyd-Evans, Emyr  ORCID: https://orcid.org/0000-0002-3626-1611, Morgillo, Carmine M., Mortenson, Paul N., O'Reilly, Marc, Richardson, Caroline J., Schöpf, Patrick, Tams, Daniel M., Waller-Evans, Helen ORCID: https://orcid.org/0000-0003-4133-6064, Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377, Whibley, Stuart, Williams, Pamela A. and Johnson, Christopher N.
2025.
High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1.
Structure
33
(8)
, pp. 1374-1385.
10.1016/j.str.2025.05.014
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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.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Biosciences Research Institutes & Centres > Medicines Discovery Institute (MDI) Schools > Medicine |
| Publisher: | Elsevier |
| ISSN: | 0969-2126 |
| Date of First Compliant Deposit: | 30 June 2025 |
| Date of Acceptance: | 22 May 2025 |
| Last Modified: | 23 Sep 2025 12:52 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/179428 |
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