Structural, molecular, and architectural principles of cell signaling
Associate Adjunct Professor
Skaggs School of Pharmacy and Pharmaceutical Sciences
Mammalian cells process information via a vast network of dynamic, context-dependent molecular interactions to maintain homeostasis, respond to the outside cues, and make cell fate decisions. Breakdowns in intracellular communication invariably accompany diseases, while therapeutic agents selectively target nodes in the communication network to bring it back to a balanced state. Our research seeks understanding of cellular information processing from computational, structural, and network biology perspectives, starting from ligand binding to surface receptors and extending all the way to cellular morphogenesis. We develop approaches for accurate computational prediction of transient interactions of proteins and chemicals with conformationally variable protein interfaces, and apply these approaches to important cell signaling targets. This is complemented by experimental work aimed at interface mapping, target characterization, structure determination, and identification of bioactive molecules. Furthermore, inspired by the philosophy of "understanding-by-building", and in order to bridge the gap between molecular level and cellular level phenomena, we develop system-level computational models of cell signaling downstream of selected targets. 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 GEMs, a novel family of non-canonical signaling molecules that link heterotrimeric G protein signaling to non-GPCR receptors.
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
Postdoctoral training: Computational Structural Biology (2004-2009), The Scripps Research Institute, La Jolla, CA
Leadership: Associate Founding Director, UCSD Center for Network Medicine.
- 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 recognition via a combination of molecular modeling with functional and biochemical assays and X-ray crystallography.
- 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.
- 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]
- Ngo, T., A.V. Ilatovskiy, A.G. Stewart, J.L.J. Coleman, F.M. McRobb, R.P. Riek, R.M. Graham, R. Abagyan, I. Kufareva*, and N.J. Smith, Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nature Chemical Biology, 2017, 13(2), 235-242 [*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
- HIV and AIDS: anti-HIV biologics targeting chemokine receptors CCR5 and CXCR4
- 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