- ASSOCIATE PROFESSOR Structural and Chemical Biology
- Computational Biology
- Computer Simulation
- Drug Design and Discovery
- Mathematical and Computational Biology
- Membrane Proteins/Channels
- Opioid/Cannabinoid Receptors
- Protein Complexes
- Protein Structure/Function
- Signal Transduction
- Structural Biology
- Theoretical Biology
- Theoretical Biophysics
M.S., University of Naples 'Federico II'
B.S., University of Naples 'Federico II'
Ph.D., II University of Naples
Postdoc, Molecular Research Institute
Dr. Filizola is a dedicated leader in computational biophysics of membrane proteins, with a special focus on the family of cell surface proteins called G protein-coupled receptors (GPCRs), which are the targets for about half of all currently used drugs. A second important line of investigation is on platelet integrin aIIbb3. Her computational methodologies are closely intertwined with collaborative experimental investigations to provide new and biologically relevant insights about the ligand-induced transmission of the signal from the exterior to the interior of the cell membrane, giving rise to new hypotheses to guide further experimental inquiry. Since the start of her academic appointment in July 2007, Dr. Filizola has been actively engaged in and is continuously making important contributions to academic research and educational activities at Mount Sinai as well as in the scientific community in general. As such, she has recently been elected a worthy recipient of the 2008 Harold and Golden Lamport Award for Excellence in Basic Research, a prestigious award given to tenure-track Assistant Professors at Mount Sinai who demonstrate exceptional potential for making significant contributions in the early stage of their academic career.
2009 - present
Independent Scientist Award (KO2)
The Doctor Harold and Golden Lamport Award for Excellence in Basic Research
Mount Sinai School of Medicine
National Research Service Award T32 DA07135
National Institute on Drug Abuse (NIDA)
Title of European Doctor in Biotechnology
European Association for Higher Education in Biotechnology
Computational Biophysics of Membrane Proteins
For more information, please visit the Filizola Laboratory website.
The overall goal of our research is to achieve a detailed mechanistic understanding of signal transduction processes triggered by molecular recognition by means of computational methodologies that range from bioinformatics to modeling and simulation. The strength of our research relies on the integration of these computational methodologies with collaborative experimental approaches to provide valuable mechanistic interpretations at the molecular level of the ligand-induced transmission of the signal to the inner side of the cell membrane. While our research is driven by the exploration and improvement of computational methods to characterize generalizable mechanisms of molecular recognition and signal transduction, we are excited by the contributions that our computational and modeling efforts make to the experimental field through the generation of new testable hypotheses. Current major research activities in the lab include:
1) Structural Aspects of Oligomerization in the Function of G Protein-Coupled Receptors (GPCRs): Considerable evidence has accumulated in recent years suggesting that GPCRs associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction, and lifetime of such receptor complexes in living cells remain topics of intense debate. We are currently designing computational strategies to assess the spatial and temporal organization of GPCRs in explicit lipid bilayers, their variability across receptor subtypes, and their possible modulation by ligands and/or cell-specific lipid compositions. These aspects need to be addressed to clarify the functional role of GPCR complexes.
2) Exploration of Membrane Protein Processes Using Enhanced Sampling Methods: We are investigating new ways to efficiently explore the conformational space of GPCRs (both monomers and dimers/oligomers), and to generate novel testable hypotheses of molecular mechanisms underlying receptor function. Specifically, we are validating the efficiency of various enhanced sampling methods in predicting ligand-specific activated states and/or likely interfaces of oligomerization that agree with experimental data.
3) Elucidation of integrin allostery and bidirectional signaling (in collaboration with Dr. Barry Coller at Rockefeller University): We are continuing our collaborative efforts to improve current understanding of the molecular mechanism(s) of αIIbβ3 integrin activation and ligand binding at an atomic scale. This information is essential to the discovery/designof more effective anti-thrombotic drugs and our teamwork has so far proven to be very successful in this direction.
4) Dynamic mechanisms of GPCRs targeted by drugs of abuse (in collaboration with Dr. Jonathan Javitch at Columbia University and Dr. Lakshmi Devi at MSSM): Our computational research takes advantage of cutting-edge developments in theory and experiments to obtain rigorous mechanistic insight, at an unprecedented level of molecular detail, into the structure, spatio-temporal organization, and dynamics of opioid receptors in the membrane, thus broadening current understanding of opioid receptor-biased agonism. Specifically, we will contribute structural and dynamic information regarding sparsely-populated states of opioid receptors that are currently impossible or difficult to retrieve experimentally, thereby generating testable hypotheses of how, at the molecular level, different opioids induce differential oligomerization and signaling, leading to the specific behavioral effects of the drugs. Experimental validation of these computational predictions, attained through long-standing collaborations, will advance our current understanding of fundamental basic mechanisms of opioid receptor function, and pave the way to novel therapeutic strategies against drug abuse and addiction.
Scarabelli G, Provasi D, Negri A, Filizola M. Bioactive conformations of two seminal delta opioid receptor penta-peptides inferred from free-energy profiles. Biopolymers 2013 Apr;.
Negri A, Rives ML, Caspers MJ, Prisinzano TE, Javitch JA, Filizola M. Discovery of a Novel Selective Kappa-Opioid Receptor Agonist Using Crystal Structure-Based Virtual Screening. Journal of chemical information and modeling 2013 Mar;.
Coudray N, Valvo S, Hu M, Lasala R, Kim C, Vink M, Zhou M, Provasi D, Filizola M, Tao J, Fang J, Penczek PA, Ubarretxena-Belandia I, Stokes DL. Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy. Proceedings of the National Academy of Sciences of the United States of America 2013 Feb; 110(6).
Filizola M, Devi LA. Grand opening of structure-guided design for novel opioids. Trends in pharmacological sciences 2013 Jan; 34(1).
Negri A, Li J, Naini S, Coller BS, Filizola M. Structure-based virtual screening of small-molecule antagonists of platelet integrin αIIbβ3 that do not prime the receptor to bind ligand. Journal of computer-aided molecular design 2012 Sep; 26(9).
Johnston JM, Wang H, Provasi D, Filizola M. Assessing the relative stability of dimer interfaces in g protein-coupled receptors. PLoS computational biology 2012; 8(8).
Filizola M, Devi LA. Structural biology: How opioid drugs bind to receptors. Nature 2012 May; 485(7398).
Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS. Structure-Guided Design of a High-Affinity Platelet Integrin αIIbβ3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS. Science Translational Medicine 2012 Mar; 4(125).
Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD, Brezina V, Sealfon SC, Filizola M, González-Maeso J, Logothetis DE. Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 2011 Nov; 147(5).
Provasi D, Artacho MC, Negri A, Mobarec JC, Filizola M. Ligand-induced modulation of the free-energy landscape of G protein-coupled receptors explored by adaptive biasing techniques. PLoS computational biology 2011 Oct; 7(10).
Johnston JM, Filizola M. Showcasing modern molecular dynamics simulations of membrane proteins through G protein-coupled receptors. Current opinion in structural biology 2011 Aug; 21(4).
Johnston JM, Aburi M, Provasi D, Bortolato A, Urizar E, Lambert NA, Javitch JA, Filizola M. Making structural sense of dimerization interfaces of delta opioid receptor homodimers. Biochemistry 2011 Mar; 50(10).
Wang H, Barreyro L, Provasi D, Djemil I, Torres-Arancivia C, Filizola M, Ubarretxena-Belandia I. Molecular determinants and thermodynamics of the amyloid precursor protein transmembrane domain implicated in Alzheimer's disease. Journal of molecular biology 2011 May; 408(5).
Golebiewska U, Johnston JM, Devi L, Filizola M, Scarlata S. Differential response to morphine of the oligomeric state of μ-opioid in the presence of δ-opioid receptors. Biochemistry 2011 Apr; 50(14).
Provasi D, Johnston JM, Filizola M. Lessons from free energy simulations of delta-opioid receptor homodimers involving the fourth transmembrane helix. Biochemistry 2010 Aug; 49(31).
Filizola M. Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?. Life sciences 2010 Apr; 86(15-16).
Khelashvili G, Dorff K, Shan J, Camacho-Artacho M, Skrabanek L, Vroling B, Bouvier M, Devi LA, George SR, Javitch JA, Lohse MJ, Milligan G, Neubig RR, Palczewski K, Parmentier M, Pin JP, Vriend G, Campagne F, Filizola M. GPCR-OKB: the G Protein Coupled Receptor Oligomer Knowledge Base. Bioinformatics (Oxford, England) 2010 Jul; 26(14).
Zhu J, Zhu J, Negri A, Provasi D, Filizola M, Coller BS, Springer TA. Closed headpiece of integrin αIIbβ3 and its complex with an αIIbβ3-specific antagonist that does not induce opening. Blood 2010 Dec; 116(23).
Provasi D, Bortolato A, Filizola M. Exploring molecular mechanisms of ligand recognition by opioid receptors with metadynamics. Biochemistry 2009 Oct; 48(42).
Provasi D, Filizola M. Putative active states of a prototypic g-protein-coupled receptor from biased molecular dynamics. Biophysical journal 2010 May; 98(10).
González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 2008 Mar; 452(7183).
Mobarec JC, Sanchez R, Filizola M. Modern homology modeling of G-protein coupled receptors: which structural template to use?. Journal of medicinal chemistry 2009 Aug; 52(16).
Guo W, Urizar E, Kralikova M, Mobarec JC, Shi L, Filizola M, Javitch JA. Dopamine D2 receptors form higher order oligomers at physiological expression levels. The EMBO journal 2008 Sep; 27(17).
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Filizola did not report having any of the following types of financial relationships with industry during 2012 and/or 2013: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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