9HJ6

TRPML1 in complex with compound 2

This is a non-PDB format compatible entry.

Summary for 9HJ6

• Entry DOI: 10.2210/pdb9hj6/pdb
• Related: 9HJ8 9HL3 9HL4 9HL6 9HL8 9HLA 9HLB 9HLC 9HLD
• EMDB information: 52210 52211 52242 52243 52245 52246 52248 52249 52250 52251
• Descriptor: Mucolipin-1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate, ... (8 entities in total)
• Functional Keywords: ion channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 291098.72

Authors

Reeks, J.,Mahajan, P.,Clark, M.,Cowan, S.R.,Di Daniel, E.,Earl, C.P.,Fisher, S.,Holvey, R.S.,Jackson, S.M.,Lloyd-Evans, E.,Morgillo, C.M.,Mortenson, P.N.,O'Reilly, M.,Richardson, C.J.,Schopf, P.,Tams, D.M.,Waller-Evans, H.,Ward, S.E.,Whibley, S.,Williams, P.A.,Johnson, C.N. (deposition date: 2024-11-28, release date: 2025-06-04, Last modification date: 2025-12-17)

Primary citation

Reeks, J.,Mahajan, P.,Clark, M.,Cowan, S.R.,Di Daniel, E.,Earl, C.P.,Fisher, S.,Holvey, R.S.,Jackson, S.M.,Lloyd-Evans, E.,Morgillo, C.M.,Mortenson, P.N.,O'Reilly, M.,Richardson, C.J.,Schopf, P.,Tams, D.M.,Waller-Evans, H.,Ward, S.E.,Whibley, S.,Williams, P.A.,Johnson, C.N.
High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1.
Structure, 33:1374-1385.e7, 2025

PubMed 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.

PubMed: 40532704
DOI: 10.1016/j.str.2025.05.014

Experimental method

ELECTRON MICROSCOPY (2.3 Å)