6NR3

Cryo-EM structure of the TRPM8 ion channel in complex with high occupancy icilin, PI(4,5)P2, and calcium

PDB DOI: https://doi.org/10.2210/pdb6NR3/pdb
EM Map EMD-0488: EMDB EMDataResource

Classification: TRANSPORT PROTEIN
Organism(s): Ficedula albicollis
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2019-01-22 Released: 2019-02-20
Deposition Author(s): Yin, Y., Le, S.C., Hsu, A.L., Borgnia, M.J., Yang, H., Lee, S.-Y.
Funding Organization(s): National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)

Experimental Data Snapshot

Method: ELECTRON MICROSCOPY
Resolution: 3.40 Å
Aggregation State: PARTICLE
Reconstruction Method: SINGLE PARTICLE

wwPDB Validation 3D Report Full Report

This is version 1.2 of the entry. See complete history.

Literature

Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel.

Yin, Y., Le, S.C., Hsu, A.L., Borgnia, M.J., Yang, H., Lee, S.Y.

(2019) Science 363

PubMed: 30733385 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1126/science.aav9334
Primary Citation of Related Structures:
6NR2, 6NR3, 6NR4

PubMed Abstract:
Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca ²⁺)-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP ₂), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP ₂, and Ca ²⁺, as well as in complex with the menthol analog WS-12 and PIP ₂ Our structures reveal the binding sites for cooling agonists and PIP ₂ in TRPM8. Notably, PIP ₂ binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP ₂ and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

Organizational Affiliation

Department of Biochemistry, Duke University School of Medicine, Durham, NC, 27710, USA.

Macromolecule Content

Total Structure Weight: 525.64 kDa
Atom Count: 25,180
Modelled Residue Count: 3,416
Deposited Residue Count: 4,540
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Transient receptor potential cation channel subfamily M member 8	A, B, C, D	1,135	Ficedula albicollis	Mutation(s): 0 Gene Names: TRPM8
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
KXP Query on KXP Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain I [auth B] SDF format, chain L [auth C] SDF format, chain O [auth D] MOL2 format, chain F [auth A] MOL2 format, chain I [auth B] MOL2 format, chain L [auth C] MOL2 format, chain O [auth D]	F [auth A], I [auth B], L [auth C], O [auth D]	(2S)-1-{[(R)-hydroxy{[(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl icosa-5,8,11,14-tetraenoate C₄₇ H₈₅ O₁₉ P₃ CNWINRVXAYPOMW-AUBJPSKUSA-N		Interactions Focus chain F [auth A] Focus chain I [auth B] Focus chain L [auth C] Focus chain O [auth D] Interactions & Density Focus chain F [auth A] Focus chain I [auth B] Focus chain L [auth C] Focus chain O [auth D]
KX7 Query on KX7 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] SDF format, chain K [auth C] SDF format, chain N [auth D] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] MOL2 format, chain K [auth C] MOL2 format, chain N [auth D]	E [auth A], H [auth B], K [auth C], N [auth D]	Icilin C₁₆ H₁₃ N₃ O₄ RCEFMOGVOYEGJN-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain H [auth B] Focus chain K [auth C] Focus chain N [auth D] Interactions & Density Focus chain E [auth A] Focus chain H [auth B] Focus chain K [auth C] Focus chain N [auth D]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain J [auth B] SDF format, chain M [auth C] SDF format, chain P [auth D] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] MOL2 format, chain M [auth C] MOL2 format, chain P [auth D]	G [auth A], J [auth B], M [auth C], P [auth D]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain J [auth B] Focus chain M [auth C] Focus chain P [auth D] Interactions & Density Focus chain G [auth A] Focus chain J [auth B] Focus chain M [auth C] Focus chain P [auth D]