Vladimir Yarov-Yarovoy, Ph.D.
My research interests and expertise encompass neuroscience, protein structure, computational biology, and evolution. Main focus of my research group is on structure and function studies of voltage-gated ion channels, computational design and chemical synthesis of subtype-specific modulators of voltage-gated ion channels, development of computational methods for membrane protein structure prediction and design, and analysis of evolution of human voltage-gated ion channels.
Function and modulation of neuronal sodium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in neurons - the basis for many aspects of signal transduction, learning, memory and physiological regulation. Mutations in neuronal voltage-gated sodium channel genes are responsible for various human neurological disorders. Furthermore, human neuronal voltage-gated sodium channels are primary targets of therapeutic drugs used as local anesthetics and for treatment of neurological and cardiac disorders. My first project is focusing on studying of neuronal voltage-gated sodium channels structure, function, and modulation in order to design new therapeutically useful drugs for treatment of pain and epilepsy. Serious, chronic pain affects at least 116 million Americans each year and epilepsy affects nearly 3 million Americans and 50 million people Worldwide. However, the treatment of chronic pain and epilepsy remains a major unmet medical need because the use of currently available drugs is limited due to incomplete efficacy and/or significant side effects. Considerable efforts by pharmaceutical industry toward identifying selective inhibitors of one or more of Nav channel subtypes did not generate any genuinely subtype selective blockers and none are currently advancing through clinical trials. My laboratory uses an innovative approach to design novel subtype selective Nav channel blocking drugs with high efficacy and minimum side effects. Novel drugs will be tested using methods of electrophysiology, biochemistry, and molecular biology. This project will provide key structural information on the molecular basis of neuronal voltage-gated sodium channels function and its interaction with therapeutically useful subtype-specific modulators. Understanding of function and modulation of the neuronal voltage-gated sodium channels on structural level will give us profound insights into the fundamental mechanisms underlying neuromodulation and signal transduction.
Over the past decade, there has been significant progress in determining membrane protein structures in general and ion channel structures in particular using x-ray crystallography methods. However, it is still very difficult to obtain high-resolution structural information about these proteins. My second project is focusing on further development of the Rosetta-Membrane computational method for high-resolution membrane protein structure prediction and design. I developed the original Rosetta-Membrane method for membrane protein structure prediction in collaboration with David Baker's group at the University of Washington and applied it for modeling of membrane proteins in general and ion channels in particular. I now propose to further improve accuracy of the Rosetta-Membrane method and expand its capabilities to design membrane proteins with new functions.
Evolution of ion channels from bacteria to human took several billion years and while there are basic features that are common to bacterial and human ion channels, such as pore-forming and/or voltage-sensing domains, there are abundance of unique features in every human ion channel family that are absent in bacterial ion channels and have been designed through evolutionary time to accomplish highly specific functions. My third project is focusing on exploring evolution of human voltage-gated ion channels using available prokaryotic and eukaryotic genomes and high-resolution ion channels structures. Human ion channel family is ranking third in a number of family members after the G protein coupled receptors and the protein kinases. To identify the mechanisms by which historical mutations generated distinct human ion channel functions, it is essential to compare proteins through evolutionary time. Moreover, reconstruction of key intermediate ancestors of ion channels by computational structural design can further advance our understanding of evolution of human ion channel function. Previously, I used bioinformatics based analysis of available high-resolution membrane proteins structures to derive parameters of membrane environment-specific scoring function used in the Rosetta-Membrane method. I now propose to analyze evolution of human voltage-gated sodium channels using phylogenetic trees and multiple sequence alignments of homologous sequences and correlate it with available structural and functional data. I will use the Rosetta-Membrane method to predict structures of human ion channels for which high-resolution structures are not available. Mapping of evolutionary information onto human voltage-gated sodium channel structures will give us significant new insights into evolution of their structure and function.
- Biophysical Society
- Protein Society
Nguyen PT, Nguyen HM, Wagner KM, Stewart RG, Singh V, Thapa P, Chen Y-J, Lillya MW, Ton AT, Kondo R, Ghetti A, Pennington MW, Hammock BD, Griffith TN, Sack JT, Wulff H, Yarov-Yarovoy V (2022) Computational design of peptides to target Nav1.7 channel with high potency and selectivity for the treatment of pain. bioRxiv. doi: 10.1101/2022.07.21.500925
Maly J, Emigh AM, DeMarco KR, Furutani K, Sack JT, Clancy CE, Vorobyov I, Yarov-Yarovoy V (2022) Structural modeling of the hERG potassium channel and associated drug interactions. Front Pharmacol. 13:966463. doi: 10.3389/fphar.2022.966463.
Nguyen PT and Yarov-Yarovoy V (2022) Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels. Front Pharmacol 13: 842032. doi: 10.3389/fphar.2022.842032.
Ledford HA, Ren L, Thai PN, Park S, Timofeyev V, Sirish P, Xu W, Emigh AM, Priest JR, Perez MV, Ashley EA, Yarov-Yarovoy V, Yamoah EN, Zhang XD, Chiamvimonvat N (2022) Disruption of protein quality control of the human ether-à-go-go related gene K + channel results in profound long QT syndrome. Heart Rhythm. S1547-5271(21)02221-9. doi: 10.1016/j.hrthm.2021.10.005.
Pumroy RA, Protopopova AD, Fricke TC, Lange IU, Haug FM, Nguyen PT, Gallo PN, Sousa BB, Bernardes GJL, Yarov-Yarovoy V, Leffler A, Moiseenkova-Bell VY (2022) Structural insights into TRPV2 activation by small molecules. Nat Commun. 13(1):2334. doi: 10.1038/s41467-022-30083-3.
George K, Lopez-Mateos D, Abd El-Aziz TM, Xiao Y, Kline J, Bao H, Raza S, Stockand JD, Cummins TR, Fornelli L, Rowe MP, Yarov-Yarovoy V, Rowe AH (2022) Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module. Front Pharmacol. 13:846992. doi: 10.3389/fphar.2022.846992.
Mazola Y, Márquez Montesinos JCE, Ramírez D, Zúñiga L, Decher N, Ravens U, Yarov-Yarovoy V, González W (2022) Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach. Pharmaceutics 14(7):1356. doi: 10.3390/pharmaceutics14071356.
Koehler Leman J, Lyskov S, Lewis SM, Adolf-Bryfogle J, Alford RF, Barlow K, Ben-Aharon Z, Farrell D, Fell J, Hansen WA, Harmalkar A, Jeliazkov J, Kuenze G, Krys JD, Ljubetič A, Loshbaugh AL, Maguire J, Moretti R, Mulligan VK, Nance ML, Nguyen PT, Ó Conchúir S, Roy Burman SS, Samanta R, Smith ST, Teets F, Tiemann JKS, Watkins A, Woods H, Yachnin BJ, Bahl CD, Bailey-Kellogg C, Baker D, Das R, DiMaio F, Khare SD, Kortemme T, Labonte JW, Lindorff-Larsen K, Meiler J, Schief W, Schueler-Furman O, Siegel JB, Stein A, Yarov-Yarovoy V, Kuhlman B, Leaver-Fay A, Gront D, Gray JJ, Bonneau R (2021) Ensuring scientific reproducibility in bio-macromolecular modeling via extensive, automated benchmarks. Nat Commun 12(1):6947. doi: 10.1038/s41467-021-27222-7.
Xu L, Zhang H, Wang Y, Lu X, Zhao Z, Ma C, Yang S, Yarov-Yarovoy V, Tian Y, Zheng J, Yang F (2021) De Novo Design of Peptidic Positive Allosteric Modulators Targeting TRPV1 with Analgesic Effects. Adv Sci (Weinh):e2101716. doi: 10.1002/advs.202101716.
DeMarco KR, Yang PC, Singh V, Furutani K, Dawson JRD, Jeng MT, Fettinger JC, Bekker S, Ngo VA, Noskov SY, Yarov-Yarovoy V, Sack JT, Wulff H, Clancy CE, Vorobyov I (2021) Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline. J Mol Cell Cardiol. 158: 163-177. doi: 10.1016/j.yjmcc.2021.05.015.
Kisiela DI, Magala P, Interlandi G, Carlucci LA, Ramos A, Tchesnokova V, Basanta B, Yarov-Yarovoy V, Avagyan H, Hovhannisyan A, Thomas WE, Stenkamp RE, Klevit RE, Sokurenko EV (2021) Toggle switch residues control allosteric transitions in bacterial adhesins by participating in a concerted repacking of the protein core. PLoS Pathog. 17(4): e1009440. doi: 10.1371/journal.ppat.1009440.
Unger EK, Keller JP, Altermatt M, Liang R, Matsui A, Dong C, Hon OJ, Yao Z, Sun J, Banala S, Flanigan ME, Jaffe DA, Hartanto S, Carlen J, Mizuno GO, Borden PM, Shivange AV, Cameron LP, Sinning S, Underhill SM, Olson DE, Amara SG, Temple Lang D, Rudnick G, Marvin JS, Lavis LD, Lester HA, Alvarez VA, Fisher AJ, Prescher JA, Kash TL, Yarov-Yarovoy V, Gradinaru V, Looger LL, Tian L. (2020) Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning. Cell 183(7): 1986-2002.e26. doi: 10.1016/j.cell.2020.11.040.
Ledford HA, Park S, Muir D, Woltz RL, Ren L, Nguyen PT, Sirish P, Wang W, Sihn CR, George AL, Knollmann BC, Yamoah EN, Yarov-Yarovoy V, Zhang XD, Chiamvimonvat N. (2020) Different arrhythmia-associated calmodulin mutations have distinct effects on cardiac SK channel regulation. J Gen Physiol. 152(12): e202012667. doi: 10.1085/jgp.202012667.
Vu S, Singh V, Wulff H, Yarov-Yarovoy V, Zheng J. (2020) New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket. Elife 9: e62039. doi: 10.7554/eLife.62039.
Yang F, Xu L, Lee BH, Xiao X, Yarov-Yarovoy V, Zheng J. (2020) An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel. Adv Sci 7(20): 2000575. doi: 10.1002/advs.202000575.
Koehler Leman J, Weitzner BD, Renfrew PD, Lewis SM, Moretti R, Watkins AM, Mulligan VK, Lyskov S, Adolf-Bryfogle J, Labonte JW, Krys J; Yarov-Yarovoy V (RosettaCommons Consortium), Bystroff C, Schief W, Gront D, Schueler-Furman O, Baker D, Bradley P, Dunbrack R, Kortemme T, Leaver-Fay A, Strauss CEM, Meiler J, Kuhlman B, Gray JJ, Bonneau R. (2020) Better together: Elements of successful scientific software development in a distributed collaborative community. PLoS Comput Biol. 16(5): e1007507. doi: 10.1371/journal.pcbi.1007507.
Li G, Woltz RL, Wang CY, Ren L, He PX, Yu SD, Liu XQ, Yarov-Yarovoy V, Hu D, Chiamvimonvat N, Wu L. (2020) Gating Properties of Mutant Sodium Channels and Responses to Sodium Current Inhibitors Predict Mexiletine-Sensitive Mutations of Long QT Syndrome 3. Front Pharmacol 11: 1182. doi: 10.3389/fphar.2020.01182.
Fletcher-Taylor S, Thapa P, Sepela RJ, Kaakati R, Yarov-Yarovoy V, Sack JT, Cohen BE (2020) Distinguishing Potassium Channel Resting State Conformations in Live Cells with Environment-Sensitive Fluorescence. ACS Chem Neurosci. Online ahead of print. doi: 10.1021/acschemneuro.0c00276.
Perez-Flores MC, Lee JH, Park S, Zhang XD, Sihn CR, Ledford HA, Wang W, Kim HJ, Timofeyev V, Yarov-Yarovoy V, Chiamvimonvat N, Rabbitt RD, Yamoah EN (2020) Cooperativity of Kv7.4 channels confers ultrafast electromechanical sensitivity and emergent properties in cochlear outer hair cells. Sci Adv. 6(15): eaba1104. doi: 10.1126/sciadv.aba1104.
Rudell JC, Borges LS, Yarov-Yarovoy V, Ferns M (2020) The MX-Helix of Muscle nAChR Subunits Regulates Receptor Assembly and Surface Trafficking. Front Mol Neurosci. 13: 48. doi: 10.3389/fnmol.2020.00048.
Yang PC, DeMarco KR, Aghasafari P, Jeng MT, Dawson JRD, Bekker S, Noskov SY, Yarov-Yarovoy V, Vorobyov I, Clancy CE (2020) A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm. Circ Res. 126(8): 947-964. doi: 10.1161/CIRCRESAHA.119.316404.
Turner M, Anderson DE, Bartels P, Nieves-Cintron M, Coleman AM, Henderson PB, Man KNM, Tseng PY, Yarov-Yarovoy V, Bers DM, Navedo MF, Horne MC, Ames JB, Hell JW (2020) α-Actinin-1 promotes activity of the L-type Ca2+ channel Cav 1.2. EMBO J. 39(5): e102622. doi: 10.15252/embj.2019102622.
Craig RA 2nd, Garrison CE, Nguyen PT, Yarov-Yarovoy V**, Du Bois J** (2020) Veratridine: A Janus-Faced Modulator of Voltage-Gated Sodium Ion Channels. ACS Chem Neurosci. 11(3): 418-426. doi: 10.1021/acschemneuro.9b00621.
Shim H, Brown BM, Singh L, Singh V, Fettinger JC, Yarov-Yarovoy V, Wulff H (2019) The Trials and Tribulations of Structure Assisted Design of KCa Channel Activators. Front Pharmacol. 10:972. doi: 10.3389/fphar.2019.00972.
Yarov-Yarovoy V, DeCaen PG (2019) The Sodium Channel Voltage Sensor Slides to Rest. Trends Pharmacol Sci. pii: S0165-6147(19) 30195-6. doi: 10.1016/j.tips.2019.08.009.
Ng LCT, Vien TN, Yarov-Yarovoy V, DeCaen PG (2019) Opening TRPP2 (PKD2L1) requires the transfer of gating charges. Proc Natl Acad Sci USA 116(31): 15540-15549. doi: 10.1073/pnas.1902917116.
Dong Y, Yin Y, Vu S, Yang F, Yarov-Yarovoy V, Tian Y, Zheng J (2019) A distinct structural mechanism underlies TRPV1 activation by piperine. Biochem Biophys Res Commun. 516(2): 365-372. doi: 10.1016/j.bbrc.2019.06.039.
Yin Y, Dong Y, Vu S, Yang F, Yarov-Yarovoy V, Tian Y, Zheng J (2019) Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers. Br J Pharmacol. 176: 3364-3377. doi: 10.1111/bph.14766.
Kimball IH, Nguyen PT, Olivera BM, Sack JT, Yarov-Yarovoy V (2019) Molecular Determinants of μ-Conotoxin KIIIA interaction with the Voltage-Gated Sodium Channel Nav1.7. bioRxiv. doi: https://doi.org/10.1101/654889.
Rudell JB, Maselli RA, Yarov-Yarovoy V, Ferns MJ (2019) Pathogenic effects of agrin V1727F mutation are isoform-specific and decrease its expression and affinity for HSPGs and LRP4. Hum Mol Genet. 28(16): 2648-2658. doi: 10.1093/hmg/ddz081.
Heeney DD, Yarov-Yarovoy V, Marco ML (2019) Sensitivity to the two peptide bacteriocin plantaricin EF is dependent on CorC, a membrane-bound, magnesium/cobalt efflux protein. Microbiologyopen. 2019 Mar 19:e827. doi: 10.1002/mbo3.827. [Epub ahead of print].
- University of Washington Royalty Research Fund Award, University of Washington
- National Institutes of Health Research Career Development Award
- Biophysical Society Graduate Student Award
Collaborators at UC Davis
- Department of Anesthesiology and Pain Medicine - Scott Fishman
- Department of Biochemistry and Molecular Medicine - Kit Lam, Justin Siegel, Lin Tian, and John Voss
- Department of Biomedical Engineering - Marc Facciotti
- Department of Cell Biology and Human Anatomy - Paul Fitzgerald
- Department of Internal Medicine - Nipavan Chiamvimonvat
- Department of Molecular and Cellular Biology - Jonathan Scholey
- Department of Neurobiology, Physiology and Behavior - James Trimmer
- Department of Pharmacology - Donald Bers, Colleen Clancy, Elva Diaz, and Heike Wulff
- Department of Physiology and Membrane Biology - Pete Cala, Michel Ferns, Alla Fomina, Jon Sack, and Jie Zheng
Collaborators Outside of UC Davis
- City College of New York - Themis Lazaridis
- Johns Hopkins University - Mark Donowitz and Jeff Gray
- National Institutes of Health - Kenton Swartz
- Royal Melbourne Institute of Technology (Australia) - Toby Allen
- Stanford University - Justin Du Bois
- University of Calgary (Canada) - Sergei Noskov
- University of California Berkeley - Ehud Isacoff
- University of California San Francisco - Bill DeGrado and Daniel Minor
- University of Chicago - Benoit Roux
- University of Copenhagen (Denmark) - Stine Pedersen
- University of Innsbruck (Austria) - Bernhard Flucher and Joerg Striessnig
- University of Utah - Baldomero Olivera
- University of Washington - David Baker, William Catterall, and Allan Rettie
- Vanderbilt University - Jens Meiler
- Weizmann Institute of Science (Israel) - Sarel Fleishman