Architectural Principles of Cell Signaling
Associate Adjunct Professor
Skaggs School of Pharmacy and Pharmaceutical Sciences
In health, disease, and therapy, processes that happen to humans span a wide range of scales. On the one hand, the basis for everything is in the miniscule atomic interactions governed by the first principles of physics; consequently, three-dimensional atomic-resolution molecular structure encodes in itself all the answers. However, compared to the entire proteome, structures are still a few, and even for structurally characterized proteins, extracting answers to the questions of function is nontrivial. On the other hand, even at the level of a single cell (let alone a whole organism), the tangled mess of molecular interactions is so complex that it becomes impossible to tackle with purely experimental means.
The overarching goal of our lab is to elucidate structural, molecular, and architectural principles of tumor and immune cell responses to stimuli and drugs via computational approaches. GPCRs and G proteins, the two key classes of cell signaling molecules, are the main focus of our work.
Computational structural biology of GPCRs and G proteins. Conformational plasticity of proteins, or rather the lack of methods for prediction of conformational changes that are relevant for interactions of these proteins with their ligands and effectors, are important barriers in modern computational structural biology. 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. In the past, in collaboration with the Handel lab and others, we elucidated the structural basis of ligand binding and signaling in chemokine GPCRs CXCR4 and ACKR3 (both playing a central role in progression and metastasis of numerous cancers, PNAS 2014, Science 2015, PNAS 2015, Nat Comms 2017, PLoS Biol 2020, Sci Signal 2020), CCR5 (an HIV co-receptor, Immunology 2017), and CCR2 (a promising target in inflammation, autoimmunity, and immune-oncology, Nature 2016). We also made key contributions to understanding non-receptor activation of heterotrimeric G proteins, and have solved the first structure of a G protein complexed with one such activator (PNAS 2019) in collaboration with the Ghosh and Chang labs.
Computational systems biology of GPCRs. The new direction of network-based modeling and reverse-engineering of cell signaling has been initiated in the lab only recently, but has already led to exciting findings about signaling cascades downstream of several chemokine receptors. The modeling process is based on automated system identification that is informed by multiplexed datasets obtained through spatiotemporally resolved interactomics, phosphoproteomics, or Luminex multi-analyte profiling. This work seeks decoding the principles of biological information transfer and processing, and will inform the design of multimodal therapeutic strategies in cancer and inflammatory diseases.
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), member of the NIH BPNS study section (2020-21), member of the NIH DDNS study section (2022-).
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).
- Member of the BMS graduate program
- 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.
- Ortiz Zacarías NV et al. (2021). Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2. J Med Chem. 64(5):2608-2621.
- Ngo T. et al (2020). Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity. PLoS Biol. 18(4):e3000656.
- Kufareva I. et al (2019). Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Sci Rep. 9(1):15893.
- Kalogriopoulos, N.A. et al (2019). Structural basis for GPCR-independent activation of heterotrimeric Gi proteins. PNAS 116 (33) 16394-16403.
- Zheng, Y. et al (2017). Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. Immunity 46(6) 1005-17.e5
- Gustavsson, M. et al (2017). Structural basis of ligand interaction with atypical chemokine receptor 3. Nature Communications (8) 14135
- Zheng, Y.et al (2016). Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540:458-461
- Kufareva, I. et al (2014). Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation. PNAS 111 (50) E5363-E5372
- Kufareva, I. et al (2014). Discovery of novel membrane binding structures and functions. Biochemistry and Cell Biology 92 (6) 555-563
- Kufareva, I.; Katritch, V.; Stevens, R. C.; Abagyan, R., (2014) Advances in GPCR modeling evaluated by the GPCR dock 2013 assessment: meeting new challenges. Structure 22 (8) 1120-1139
- Kufareva, I.*; Ilatovskiy, A. V.; Abagyan, R. (2012). Pocketome: an encyclopedia of small-molecule binding sites in 4D. Nucleic acids research 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