Deciphering structural bases of TRP channel inhibition as foundations for the design of new drugs

• Applicant: Dr. Arthur Neuberger
• Subject Area: Structural Biology ; Biochemistry ; Biophysics
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464295817

• Final Report Year: 2024

Final Report Abstract

Any physical or mental activity involves ion channels, which are essential for many biological processes. Ion channels are also associated with numerous human diseases, including those caused by mutations (channelopathies). Many drugs, including local anaesthetics, antianxiety agents, and sedatives, target ion channels. However, highly efficient and selective drugs are missing for many ion channels due to our limited knowledge about their molecular mechanisms of regulation. I am particularly interested in transient receptor potential (TRP) vanilloid subfamily (TRPV) channels. These polymodal sensory transducers respond to chemicals, temperature, mechanical stress, and membrane voltage and are involved in vision, taste, olfaction, hearing, touch, thermal perception, and nociception. Mutations or changes in expression of TRP channels are associated with numerous human diseases, including cardiovascular, renal, nociceptive, metabolic disorders, and cancers. Transient receptor potential (TRP) channels are versatile membrane proteins that can be divided into master regulators (gatekeepers) of ion homeostasis and sensory transducers that respond to changes in temperature (noxious/innocuous heat/old) or pungent natural compounds amongst other. Whilst the former regulate quintessential cell functions (e.g., TRPV6), the latter play an important role in our interaction with the environment and our ability to make healthy choices (e.g., TRPV1/3). When a TRP channel is activated, it undergoes conformational changes, transitioning into a state in which its transmembrane pore opens for conductance of ions that pass between extracellular and intracellular spaces. Some channels (e.g., TRPV1/3) open their pores only in response to an agonist or a physical stimulus. Other channels, like TRPV6, are permanently open.

Publications

• Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nature Communications, 12(1).
  Nadezhdin, Kirill D.; Neuberger, Arthur; Nikolaev, Yury A.; Murphy, Lyle A.; Gracheva, Elena O.; Bagriantsev, Sviatoslav N. & Sobolevsky, Alexander I.
  
• Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel. Nature Structural & Molecular Biology, 28(7), 564-572.
  Nadezhdin, Kirill D.; Neuberger, Arthur; Trofimov, Yuri A.; Krylov, Nikolay A.; Sinica, Viktor; Kupko, Nikita; Vlachova, Viktorie; Zakharian, Eleonora; Efremov, Roman G. & Sobolevsky, Alexander I.
  
• Structural mechanism of TRPV3 channel inhibition by the plant‐derived coumarin osthole. EMBO reports, 22(11).
  Neuberger, Arthur; Nadezhdin, Kirill D.; Zakharian, Eleonora & Sobolevsky, Alexander I.
  
• Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole. Nature Communications, 12(1).
  Neuberger, Arthur; Nadezhdin, Kirill D. & Sobolevsky, Alexander I.
  
• TRPV3 expression and purification for structure determination by Cryo-EM. Methods in Enzymology, 31-48. Elsevier.
  Neuberger, Arthur, Nadezhdin, Kirill D. & Sobolevsky, A.I.
  
• Dyclonine inhibition of TRPV3: From functional discovery to structural insight. Cell Calcium, 105, 102617.
  Wang, Peiyu; Mo, Xiaoyi; Li, Dongdong & Yao, Jing
  
• Structural snapshots of the mechanism of TRPV2 channel activation by small-molecule agonists. Cell Calcium, 105, 102607.
  Nadezhdin, Kirill D.; Neuberger, Arthur & Sobolevsky, Alexander I.
  
• Columbia University Postdoc Society Blog ”Unveiling the secrets of pain: decoding the structure of a human receptor for effective relief” on published paper.
  Neuberger, Arthur
  
• Human TRPV1 structure and inhibition by the analgesic SB-366791. Nature Communications, 14(1).
  Neuberger, Arthur; Oda, Mai; Nikolaev, Yury A.; Nadezhdin, Kirill D.; Gracheva, Elena O.; Bagriantsev, Sviatoslav N. & Sobolevsky, Alexander I.
  
• Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin. Nature Communications, 14(1).
  Neuberger, Arthur; Trofimov, Yury A.; Yelshanskaya, Maria V.; Khau, Jeffrey; Nadezhdin, Kirill D.; Khosrof, Lena S.; Krylov, Nikolay A.; Efremov, Roman G. & Sobolevsky, Alexander I.
  
• Molecular pharmacology of the onco-TRP channel TRPV6. Channels, 17(1).
  Neuberger, Arthur & Sobolevsky, Alexander I.
  
• Pentameric TRPV3: An artifact or a clue to channel function?. Cell Calcium, 116, 102812.
  Neuberger, Arthur & Sobolevsky, Alexander I.
  
• Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Nature Communications, 14(1).
  Neuberger, Arthur; Trofimov, Yury A.; Yelshanskaya, Maria V.; Nadezhdin, Kirill D.; Krylov, Nikolay A.; Efremov, Roman G. & Sobolevsky, Alexander I.
  
• Structural mechanisms of TRPM7 activation and inhibition. Nature Communications, 14(1).
  Nadezhdin, Kirill D.; Correia, Leonor; Narangoda, Chamali; Patel, Dhilon S.; Neuberger, Arthur; Gudermann, Thomas; Kurnikova, Maria G.; Chubanov, Vladimir & Sobolevsky, Alexander I.
  
• Structure of human TRPV4 in complex with GTPase RhoA. Nature Communications, 14(1).
  Nadezhdin, Kirill D.; Talyzina, Irina A.; Parthasarathy, Aravind; Neuberger, Arthur; Zhang, David X. & Sobolevsky, Alexander I.
  
• Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels. Communications Chemistry, 7(1).
  Trofimov, Yury A.; Krylov, Nikolay A.; Minakov, Alexander S.; Nadezhdin, Kirill D.; Neuberger, Arthur; Sobolevsky, Alexander I. & Efremov, Roman G.
  
• Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930. Cell Reports, 43(4), 114108.
  Nadezhdin, Kirill D.; Correia, Leonor; Shalygin, Alexey; Aktolun, Muhammed; Neuberger, Arthur; Gudermann, Thomas; Kurnikova, Maria G.; Chubanov, Vladimir & Sobolevsky, Alexander I.
  
• TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site. Science Advances, 10(18).
  Nadezhdin, Kirill D.; Neuberger, Arthur; Khosrof, Lena S.; Talyzina, Irina A.; Khau, Jeffrey; Yelshanskaya, Maria V. & Sobolevsky, Alexander I.