The structure of cool
December 07, 2017
A team of researchers from The Scripps Research Institute (TSRI) and Duke University has made the first determination of the atomic structure of Transient Receptor Potential Melastatin 8 (TRPM8), a molecular sensor in nerve ends that detects cold temperatures as well as menthol and other chemicals that induce cold sensations.
This finding should boost ongoing efforts by scientists to target TRPM8 therapeutically. Drug compounds that interact with the cold sensor as menthol-containing salves already do may be able to treat some forms of chronic pain and inflammation, migraines and even cancers.
Knowing the atomic structure of TRPM8 and how it reacts to cold, menthol and other stimuli should help in the design of potent and selective new drugs targeting this sensor, said study leader Gabriel C. Lander, Ph.D., associate professor at TSRI, who co-led the study with Seok-Yong Lee, Ph.D., at Duke University School of Medicine.
TSRI Associate Professor Gabriel Lander and Graduate Student Mengyu Wu led the research at The Scripps Research Institute. (Image by Madeline McCurry-Schmidt)
The discovery, published on Dec. 7, 2017 in the journal Science, is also a significant technical feat. Ever since the cold-sensing protein was first identified in 2002, teams around the world have tried but failed to determine the atomic structure of TRPM8 using X-ray crystallography, traditionally the go-to method for solving large-protein structures. Obtaining a high resolution structure of TRPM8 has posed a major challenge for structural biologists in part because of the instability of the channel when isolated from its native environment in the cellular membrane. Without membrane support, TRPM8 has a tendency to lose its structural integrity, making the target very difficult to study. The TRPM8 sensor structure is also relatively complex, being composed of four identical copies of the protein encoded by the TRPM8 gene.
For this project, Lander and co-first author Mengyu Wu, a graduate student in his laboratory, opted instead to use cryo-electron microscopy (cryo-EM), a structure determination method that is increasingly preferred for difficult structural studies. Lee and his team began by screening TRPM8 proteins from more than a dozen different animal species, including humans, mice, and birds, to find one that was likely to be best behaved for a cryo-EM study. They settled on the TRPM8 protein from a bird called the collared flycatcher.
All evidence points to the flycatcher TRPM8 working in the same way as mammalian TRPM8s, so we're confident that our structural analysis will translate directly to the human form of this sensor, Lander said.
The scientists faced many hurdles due to the inherent instability of TRPM8 outside of its native membrane environment. Even within a single day of shipping the samples from Duke to TSRI, the protein complex would start to fall apart, said Wu. The Lee lab strategically added a few stabilizing mutations to the protein so that it would be less prone to degradation . Ying Yin, a graduate student in the Lee laboratory, also went back and meticulously screened through several purification conditions to confer additional stability to the sample.
The protein also behaved differently from most of the samples that the Lander lab typically works on for electron microscopy, and it took the researchers over a year to identify the right conditions to image this challenging biomolecule.
We had to throw out the rulebook and rethink the usual approach to solving this kind of structure, said Lander.
Through these adaptations, the researchers were able to obtain the first structural glimpse of TRPM8 at an overall resolution of about 4 Angstroms (0.4 billionths of a meter). The resulting atomic model contained some surprises too. Other groups have hypothesized about the structure of TRPM8 and how it interacts with binding partners such as menthol, but what we found was that virtually all these educated guesses were pretty far off, Lander said. In particular, the binding pocket for menthol turned out to be in an unexpected location, different from the ligand binding location in other TRP sensors.
One thing this structure tells us is that TRP sensors do not all work in the same way, and so I expect that we're going to discover many new sensor mechanisms as we study more of these TRP structures, Lander said.
TRPM8 is of interest to the pharmaceutical industry in part because of the analgesic, anti-inflammatory effects it can have when activated. Moreover, variants of its gene have been linked to a predisposition to migraines, and scientists have shown that manipulating TRPM8 can cause migraine-like pain in animals.
TRPM8 also is abnormally expressed in some prostate, breast and other cancers, making it a potential chemotherapeutic target, Wu said.
Although TRPM8 is best known as a peripheral-nerve sensor of moderately cold temperatures (below about 25 C) and of cold-sensation molecules such as menthol, it is also found within many other normal tissues, even deep within the body, and its functions in those tissues remain largely unclear. A detailed understanding of TRPM8's structural interaction with its natural binding partners should lead to the development of better molecular probes that can help scientists reveal its various functions.
The Lander and Lee Laboratories are now working to better understand how TRPM8 interacts with menthol and other therapeutic binding-partner molecules.
Additional authors of the study, Structure of the cold- and menthol-sensing ion channel TRPM8, were co-first author Ying Yin, and Lejla Zubcevic and William F. Borschel, all of the Lee Laboratory.
Funding was provided by the National Institutes of Health (grants R35NS097241 and DP2EB020402).
Integrative Structural & C
Most recent headlines
09/11/2025
Dalet today announced a transformative leap forward for media operations: Agentic Artificial Intelligence (AI) that unifies the Dalet ecosystem under one natura...
23/10/2025
A deadline is looming for a new carriage deal between Verizon's Fios TV and Nexstar, with both Verizon and the pay TV-backed American Television Alliance bl...
23/10/2025
NEW YORK During a high-profile session at NAB Show New York, new survey data was shared that revealed significant public concern over artificial intelligence (A...
23/10/2025
BELLEVUE, Wash. and NEW YORK Fox Weather has tapped T-Mobile has as its preferred communications provider and announced that all Fox Weather reporters are being...
23/10/2025
PBS and Amazon Web Services have announced the network is using generative AI to provide enhanced search results to viewers on the PBS App and PBS LearningMedia...
22/10/2025
Prime Video Inks Deal To Present NFL Black Friday Game Worldwide By SVG Staff
Wednesday, October 22, 2025 - 10:06 am
Print This Story | Subscribe
Story ...
22/10/2025
NBA Tip-Off: ESPN Goes 1080p HDR End-to-End, Flipping HDR Switch on REMI and REM...
22/10/2025
FloSports Empowers Division II, III Athletic Departments With Turnkey Production...
22/10/2025
Wall Street Video Summit Debuts, Bringing Together 200 Financial Enterprise Vide...
22/10/2025
Dueling Pianos: International Chopin Piano Competition Is as Competitive as a Ba...
22/10/2025
In 1995, a young Colombian artist released an album that would change Latin pop ...
22/10/2025
Over the past few months, a photovoltaic system has been installed on a three-he...
22/10/2025
The Orion spacecraft for NASA's Artemis II mission is stacked on the Space Launch System (SLS) rocket in High Bay 3 of the Vehicle Assembly Building at Kenn...
22/10/2025
L3Harris' Hybrid SATCOM is resilient by design, offering path diversity that eliminates vulnerabilities by routing data across the best available networks i...
22/10/2025
WASHINGTON, D.C. Organizers of NAB Show New York said they are expecting more than 12,000 registered attendees from about 100 countries along with 260 exhibitor...
22/10/2025
WASHINGTON, D.C The organizers of The 2025 NAB Show New York have announced that they are expecting more than 12,000 registered attendees from about 100 countr...
22/10/2025
Masque Sound, a leading theatrical sound reinforcement, installation and design company, supplied an extensive gear package of professional-grade equipment for ...
22/10/2025
Lightware, a global leader in signal management and AV connectivity solutions, is seeing strong market momentum for the UCX-3x3-TPX-RX20, a compact transmitter-...
22/10/2025
MELVILLE, N.Y. Chyron has released PAINT 10.2, the latest update for its telestration platform, adding support for SMPTE ST 2110 IP workflows, expanding brandin...
22/10/2025
WASHINGTON Run3TV today said NBCUniversal is joining as an investor in the ATSC 3.0 Framework Authority, which develops the Run3TV NextGen TV application platfo...
22/10/2025
ATLANTA swXtch.io will feature two new networking solutions extending the company's reach across more cloud and on-prem workflows at NAB Show New York, set ...
22/10/2025
The Warner Bros. Discoverys HBO Max streaming services has increased prices for all its streaming tiers effectively immediately for new customers. Existing cust...
22/10/2025
LOS ANGELES OpenDrives has signed a new distribution partnership deal with Versatile Distribution Services (VDS) to strengthen its channel and streamline how it...
22/10/2025
WASHINGTON, D.C The organizers of The 2025 NAB Show New York have announced that they are expecting more than 12,000 registered attendees from about 100 countr...
22/10/2025
Samora Pinderhughes Brings Immersive Sound to Berklee's Signature Series The artist and composer, who's worked with Herbie Hancock, Robert Glasper, Co...
22/10/2025
BMI Day at Berklee Celebrates Composer Fil Eisler and Awards Scholarship to Stud...
22/10/2025
October 22nd, 2025 TRIBECA ANNOUNCES STAR-STUDDED LINEUP OF MEMBERSHIP EVENTS F...
22/10/2025
Rohde & Schwarz and TRUMPF cooperate in drone defense Rohde & Schwarz and TRUMPF partner to deliver a comprehensive drone defense solution combining Rohde & S...
22/10/2025
European Broadcaster Upgrades To Grass Valley's NativeIP LDX 135 Cameras And...
22/10/2025
Everyone Gets a Better Deal on Verizon with New FOX One Perk The $15 FOX One streaming service perk is yet another way Verizon continues to add savings for cu...
22/10/2025
First Look Hidden Assets Series 3
Premieres on 9th November 9:30pm on RT One & RT Player
WATCH HERE Promo Link: Hidden Assets Series 3 | RT
The Crimin...
21/10/2025
NAB New York 2025: Although AES Show Is on Its Own, Audio Will Be a Major Part o...
21/10/2025
NAB New York 2025: Business of Broadcast and Media,' Future of Content'...
21/10/2025
SVG All-Stars: Ethan Folz, Senior Director, Digital Operations and Quality of Ex...
21/10/2025
NBA on NBC/Peacock: Livestream Offers Graphic Overlays, Predictive Gaming, Ancil...
21/10/2025
NBA on NBC/Peacock: At the Front Bench With Producer Frank DiGraci and Director ...
21/10/2025
NBA on NBC/Peacock: NBC Sports, NEP Build Ultra-Flexible Production Plan That Se...
21/10/2025
Indigenous storytelling has been at the heart of the work of the Sundance Instit...
21/10/2025
Top L-R: Mysterious Skin, American Dream Second Row L-R: Little Miss Sunshine, D...
21/10/2025
Last week, Spotify and Columbia Records transformed Pier 4 at the Brooklyn Army ...
21/10/2025
SBS Learn's Dharug Ngurra resource empowers classrooms to meaningfully celeb...
21/10/2025
As global operators simplify and evolve their digital platforms, NPS improvement...
21/10/2025
Critical Design Review completion is a key milestone on the path toward Wideband Global Satellite Communications certification for the network in 2026, opening ...
21/10/2025
New Australian undersea training range to implement and improve warfighting tactics, proficiency and safety; enable joint/allied training that contributes to pr...
21/10/2025
eds3_5_jq(document).ready(function($) { $(#eds_sliderM519).chameleonSlider_2_1({...
21/10/2025
September, the beginning of autumn, brought an expected revival to the TV market, largely due to the new fall TV schedules. The time spent in front of the TV sc...
21/10/2025
Broadcast Booms with 20% Uptick vs. August, Achieving Largest Monthly
Increase ...
21/10/2025
During September, streaming's share of TV viewing in Mexico settled at 24.5%, a marginal shift of -0.5 share points from the previous month.
Disclaimer: YU...
21/10/2025
RENNES, France BBright and GlobalM have conducted a technical trial validating Ultra HD interoperability across the entire contribution chain in the cloud, achi...
The structure of cool 
