This KO2 application seeks support from NIDA for Dr. Marta Filizola's continued career development as an independent investigator. Her overall career goal is to contribute to the advancement in knowledge towards a better understanding of the molecular mechanisms underlying G-protein coupled receptor (GPCR)-mediated actions of drugs of abuse by means of computational methodologies that range from bioinformatics to modeling and simulation. In view of the recently established role and importance of GPCR oligomerization in receptor function, current research objectives of the Filizola laboratory are: a) To build refined three-dimensional (3D) models of GPCR oligomers;b) To build activated states of GPCR complexes in the interaction with their G-proteins;c) To study the dynamics of active and inactive GPCR complexes, so as to identify the molecular determinants responsible for allosteric modulation of GPCR function;d) To identify the molecular determinants responsible for the specificity of GPCR oligomerization and functional plasticity;and e) To develop, interpret and disseminate to the scientific community detailed information about the structural context of GPCR oligomerization and its experimentally determined implication for mechanisms of drug abuse. These research objectives are embodied in the proposed aims of the applicant's two currently funded NIDA projects, RO1 DA020032 and R21/R33 DA017976. In pursuit of these long-term research goals, the objectives of the current KO2 application include: 1) freeing the applicant from some teaching and administrative duties to devote nearly full time to develop further her research studies on GPCRs involved in mechanisms of drug abuse;2) advancingthe applicant's progress in becoming a leader in computational studies of GPCR dimers/oligomers;and 3) intensifying the applicant's training in experimental techniques currently used to study structure, function, and dynamics of GPCR dimers/oligomers. Career development activities proposed in this application include interactions and collaborations designed to expose the applicant to novel computational methodologies as well as molecular and biophysical experimental techniques in vitro and in vivo.
Understanding of GPCR function has recently been challenged by experimental evidence that several of these receptors are organized in the cell membrane as oligomers with unique pharmacological properties. Oligomeric models of GPCRs resulting from use of computational approaches further supported by experiments are expected to help design more effective and selective agents for therapeutic purposes.
|Ferré, Sergi; Casadó, Vicent; Devi, Lakshmi A et al. (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66:413-34|
|Johnston, Jennifer M; Filizola, Marta (2014) Beyond standard molecular dynamics: investigating the molecular mechanisms of G protein-coupled receptors with enhanced molecular dynamics methods. Adv Exp Med Biol 796:95-125|
|Johnston, Jennifer M; Filizola, Marta (2014) Differential stability of the crystallographic interfaces of mu- and kappa-opioid receptors. PLoS One 9:e90694|
|Shang, Yi; LeRouzic, Valerie; Schneider, Sebastian et al. (2014) Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions. Biochemistry 53:5140-9|
|Scarabelli, Guido; Provasi, Davide; Negri, Ana et al. (2013) Bioactive conformations of two seminal delta opioid receptor penta-peptides inferred from free-energy profiles. Biopolymers :|
|Gomes, Ivone; Fujita, Wakako; Gupta, Achla et al. (2013) Identification of a *-ýý opioid receptor heteromer-biased agonist with antinociceptive activity. Proc Natl Acad Sci U S A 110:12072-7|
|Mondal, Sayan; Johnston, Jennifer M; Wang, Hao et al. (2013) Membrane driven spatial organization of GPCRs. Sci Rep 3:2909|
|Filizola, Marta; Devi, Lakshmi A (2013) Grand opening of structure-guided design for novel opioids. Trends Pharmacol Sci 34:6-12|
|Negri, Ana; Rives, Marie-Laure; Caspers, Michael J et al. (2013) Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening. J Chem Inf Model 53:521-6|
|Fribourg, Miguel; Moreno, Jose L; Holloway, Terrell et al. (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147:1011-23|
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