Von Molekül zu Geruch: verbessertes Verständnis von Geruchsempfinden durch in silico, in vitro und in vivo Experimente

• Antragstellerin: Xiaojing Cong, Ph.D.
• Fachliche Zuordnung: Bioinformatik und Theoretische Biologie ; Biochemie ; Biophysik
• Förderung: Förderung von 2016 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 323109959

• Erstellungsjahr: 2020

Zusammenfassung der Projektergebnisse

G protein-coupled receptors (GPCRs) are the largest family of transmembrane proteins in the human genome, comprising the targets of >30% of marketed drugs. Half of the 800 human GPCRs are olfactory receptors (ORs), which enable us to detect and discriminate up to 1 trillion odors. More and more ectopically expressed ORs are also emerging as potential drug targets. The project studied the molecular mechanism of GPCR activation, using enhanced-sampling molecular dynamics simulations and sitedirected mutagenesis data. We obtained detailed understanding of the roles of agonists, antagonists, allosteric modulators, mutations, pH and sodium ions in promoting or inhibiting GPCR activation. An application on zebrafish ORs demonstrated how zebrafish detect and discriminate bile acids/salts with high precision. Finally, we established a machine learning approach that predicts the function of hundreds of ORs based on their primary sequence. The project outcome provide numerical modeling techniques as well as structural basis for the design and screening of drug candidates, odorants and odor blockers/maskers.

Projektbezogene Publikationen (Auswahl)

• “Activation dynamics of the neurotensin G protein-coupled receptor 1”, J Chem Theory Comput, 14 (2018): 4467-4473
  X Cong, S Fiorucci, J Golebiowski
  (Siehe online unter https://doi.org/10.1021/acs.jctc.8b00216)
• “Allosteric Na+-binding site modulates CXCR4 activation”, Phys Chem Chem Phys, 20 (2018): 24915-24920
  X Cong, J Golebiowski
  (Siehe online unter https://doi.org/10.1039/c8cp04134b)
• “Allosteric modulation mechanism of the mGluR5 transmembrane domain”, J Chem Inf Mod, 59 (2019): 2871-2878
  X Cong, JB Cheron, J Golebiowski, S Antonczak, F Fiorucci
  (Siehe online unter https://doi.org/10.1021/acs.jcim.9b00045)
• “Zebrafish olfactory receptors ORAs differentially detect bile acids and bile salts”, J Biol Chem, 294 (2019): 6762-6771
  X Cong, Q Zheng, JB Cheron, S Fiorucci, C Zhang, H Yu, J Golebiowski, Y Yu
  (Siehe online unter https://doi.org/10.1074/jbc.RA118.006483)
• Functions of olfactory receptors are decoded from their sequence
  X Cong, W Ren, J Pacalon, CA de March, H Matsunami, Y Yu, J Golebiowski
  (Siehe online unter https://doi.org/10.1101/2020.01.06.895540)