Structural, molecular, and architectural principles of cell signaling
Associate Adjunct Professor
Skaggs School of Pharmacy and Pharmaceutical Sciences
The long-standing goal of my work is to elucidate the structural, molecular, and architectural principles of cell signaling, including cellular responses to stimuli and drugs. We approach this challenge at multiple levels, from atomic-resolution molecular interactions to the level of cellular systems, using methods and tools of trans-scale computational biology.
At the atomic resolution level, we develop methods for accurate computational prediction of transient interactions of proteins and chemicals with conformationally variable protein interfaces, and apply these approaches to important cellular targets. This is complemented by experimental work aimed at identification of bioactive molecules, target characterization and assay development.
At the systems level, we work towards understanding the unifying engineering and architectural principles that govern intracellular signaling networks. Inspired by the philosophy of "understanding-by-building", and in collaboration with numerous experimentalists, we seek to contribute to the construction of a predictive in silico cell.
Much of our work is focused on G protein coupled receptors (e.g. chemokine receptors and SMO) because of their promise as therapeutic targets in inflammatory diseases and cancer. We also study heterotrimeric G proteins and other key transducers of GPCR-generated signals in mammalian cells.
Education: S.c. laude M.S. in Mathematics and Computer Science (1994) from Tomsk State University, Russia; Ph.D. in Computer Science (2000) from Tomsk State University, Russia
Awards and Honors: Invited lectures at the ASCEPT-MPGPCR Joint Scientific Meeting, Melbourne, Australia (2016), 5th Hawaiian GPCR workshop, Kona, Hawaii (2017), 256th ACS National Meeting, Boston, MA (2018), Gordon Research Conference on Molecular Pharmacology, Ventura, CA (2019). Mail-in reviewer for the NIH NCF study section (2017), ad hoc member of the NSF CLP PSD panel (2019), ad hoc member of the NIH BPNS study section (2020).
Postdoctoral training: Computational Structural Biology (2004-2009), The Scripps Research Institute, La Jolla, CA
Leadership: Associate Founding Director, UCSD Center for Network Medicine (2017-2020).
- Co-curricular course (SPPS 211C, founder and chair)
- Pharmaceutical Chemistry I / Advanced Organic Chemistry (SPPS 221, guest lecturer)
- Principles of Pharmaceutical Sciences and Drug Development (SPPS 263A, guest lecturer)
- Pharmaceutical Chemistry II / Physical Principles of Pharmacy (SPPS 222, 2007-2012 and 2018, with Dr. Abagyan)
- Elucidated the structural basis of receptor:chemokine binding, signaling and selectivity via a combination of molecular modeling with functional and biochemical assays and X-ray crystallography.
- Revealed the structural basis of heterotrimeric G protein activation by a non-receptor GEF.
- Developed chemical field docking for structure prediction and molecular modeling.
- Developed methods for computational protein structure prediction and annotation (e.g. protein-protein interactions, transient membrane interactions).
- Co-organized and led two community-wide assessments of modeling and docking methods for GPCRs.
- Founded the Pocketome: an encyclopedia of binding sites for small molecules and peptides in 4D.
- Ngo T, Stephens BS, Gustavsson M, Holden LG, Abagyan R, Handel TM, Kufareva I. Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity. PLoS Biol. 2020; 18(4):e3000656.
- Kufareva I, Bestgen B, Brear P, Prudent R, Laudet B, Moucadel V, Ettaoussi M, Sautel CF, Krimm I, Engel M, Filhol O, Borgne ML, Lomberget T, Cochet C, Abagyan R. Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Sci Rep. 2019; 9(1):15893.
- Kalogriopoulos, N.A., S.D. Rees, T. Ngo, N.J. Kopcho, A.V. Ilatovskiy, N. Sun, E.A. Komives, G. Chang, P. Ghosh, I. Kufareva. Structural basis for GPCR-independent activation of heterotrimeric Gi proteins. PNAS 2019: p. 201906658.
- Zheng, Y., G. W. Han, R. Abagyan, B. Wu, R.C. Stevens, V. Cherezov, I. Kufareva*, and T.M. Handel, Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. Immunity, 2017, 46(6), 1005-17.e5 [*co-corresponding author]
- Gustavsson, M., L. Wang, N. van Gils, B.S. Stephens, P. Zhang, T. Schall, S. Yang, R. Abagyan, M.R. Chance, I. Kufareva*, and T.M. Handel, Structural basis of ligand interaction with atypical chemokine receptor 3. Nature Communications, 2017, 8, 14135 [*co-corresponding author]
- Zheng, Y., L. Qin, N.V.O. Zacarías, H. de Vries, G.W. Han, M. Gustavsson, M. Dabros, C. Zhao, R.J. Cherney, P. Carter, D. Stamos, R. Abagyan, V. Cherezov, R.C. Stevens, A.P. Ijzerman, L.H. Heitman, A. Tebben, I. Kufareva*, and T.M. Handel, Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature, 2016, 540:458-461 [*co-corresponding author]
- Kufareva, I.* ; Stephens, B. S.; Holden, L. G.; Qin, L.; Zhao, C.; Kawamura, T.; Abagyan, R.; Handel, T. M., Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation. Proceedings of the National Academy of Sciences 2014, 111 (50), E5363-E5372 [*principal and co-corresponding author]
- Kufareva, I.; Lenoir, M.; Dancea, F.; Sridhar, P.; Raush, E.; Bissig, C.; Gruenberg, J.; Abagyan, R.; Overduin, M., Discovery of novel membrane binding structures and functions. Biochemistry and Cell Biology 2014, 92 (6), 555-563
- Kufareva, I.; Katritch, V.; Stevens, R. C.; Abagyan, R., Advances in GPCR modeling evaluated by the GPCR dock 2013 assessment: meeting new challenges. Structure 2014, 22 (8), 1120-1139
- Kufareva, I.*; Ilatovskiy, A. V.; Abagyan, R., Pocketome: an encyclopedia of small-molecule binding sites in 4D. Nucleic acids research 2012, 40 (D1), D535-D540 [*principal and co-corresponding author]
Pharmaceutical Industry and Biotech
- Cancer, diabetic nephropathy, cardiac fibrosis: small molecules and biologics antagonizing CCR2, CCR2 signaling pathway mapping
- Shh-dependent cancers: SMO antagonist development, SMO signaling pathway mapping
- HIV and AIDS: anti-HIV biologics targeting chemokine receptors CCR5 and CXCR4