Molecular basis of chemokine receptor signaling and antagonism
As the driving force behind cell migration, interactions of chemokines (chemotactic cytokines) with cell surface receptors play a major role in development, inflammation, and cancer. Despite the far-reaching consequences of chemokine receptor signaling, structural information on how receptors interact with chemokines, or how this interaction triggers activation of the downstream signaling pathways, has been long lacking. We seek to fill this knowledge gap and elucidate the structural basis of chemokine receptor interaction with chemokines and other molecules, understand how this interaction modifies the conformation and dynamics of the receptors, and untangle the complexities of cellular signaling downstream of receptor activation. We also take a more translational direction and design, in a rational structure-based way, small molecules and biologics capable of modulating these receptors, to serve as tools, chemical probes, and ultimately therapeutic candidates for cancer and autoimmune diseases.
- 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. Proc Natl Acad Sci U S A, 2014, 111 (50), E5363-E5372.
- Qin, L.; Kufareva, I.*; Holden, L. G.; Wang, C.; Zheng, Y.; Zhao, C.; Fenalti, G.; Wu, H.; Han, G. W.; Cherezov, V., Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science 2015, 347 (6226), 1117-1122.
- Hanes, M. S.; Salanga, C. L.; Chowdry, A. B.; Comerford, I.; McColl, S. R.; Kufareva, I.; Handel, T. M., Dual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines. J Biol Chem 2015, jbc. M115. 675108.
- Wescott, M.P., Kufareva, I., Paes, C., Goodman, J.R., Thaker, Y., Puffer, B.A., Berdougo, E., Rucker, J.B., Handel, T.M., Doranz, B.J. Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices. Proc Natl Acad Sci U S A, 2016, 113(35), 9928-33.
- 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.
- 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. Nat Comms, 2017, 8, 14135.
- 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.
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 the field of modern computational structural biology. To fully characterize the conformational plasticity landscape of protein complexes with peptides and small molecules, we created the Pocketome: an encyclopedia of binding sites for small molecules and peptides in 4D. By means of conformational pluralism, the entries in the encyclopedia provide an efficient representation of ligand recognition capabilities and induced fit in each individual site. Since the initial publication, the Pocketome not only has been constantly increased in size, but also enriched through implementation of novel and unique pocket analysis functionality. Most recently, using the Pocketome, we devised a novel metric for evaluating pharmacological similarity of G protein-coupled receptors: named GPCR-CoINPocket (for Contact-Informed Neighboring Pocket), this metric is independent of either structure of GPCRs in question, or knowledge of existing ligands. This makes it an invaluable tool for characterization of orphan GPCRs. Using the metric, we went on to characterize the pharmacological neighborhood of GPR37L1, an orphan GPCR involved in cardiovascular homeostasis, and to identify first small molecule modulators for this cryptic receptor. We seek to develop the Pocketome into a universal platform for predicting drug polypharmacology.
- Kufareva, I. *; Ilatovskiy, A. V.; Abagyan, R., Pocketome: an encyclopedia of small-molecule binding sites in 4D. Nuc Acids Res, 2012, 40 (D1), D535-D540.
- 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. Nat Chem Biol, 2017, 13(2), 235-242.
The Intranet of Cells
A eukaryotic cell is a highly organized complex system that is (i) composed of relatively simple components interacting on short spatial scales in the absence of centralized control, yet (ii) robust and adaptable in the face of environmental stress, and (iii) capable of complex behaviors in response to external stimuli. These unique properties are enabled through the interactions among a diverse repertoire of functionally specialized components (organelles or sub-organellar structures) that not only dynamically communicate with each other but can also be created, modified, and destroyed on an as-needed (ad hoc) basis.
Pilot studies suggest that the architecture and the principles of information transfer in intracellular communication are in many ways similar to those in the global communication network, the Internet, spurring the Intranet of Cells (IoC) paradigm. As in telecommunications, flexibility, evolvability and robustness in the IoC are gained at the expense of speed (a design tradeoff), and appear to be mediated by the layered protocol architecture underlying optimal functioning. Such architecture facilitates rewiring under stress, as encountered in cancer, autoimmunity, and other diseases.
In pursuing this idea, we aim to decode the Intranet of Cells, i.e. to unravel the engineering principles that govern the architecture, properties, and information transfer in the intracellular signaling networks, and to dissect them at the molecular level in a systematic, time- and space-resolved manner. This research holds promise for (i) fundamentally transforming our approach to studying cell biology, (ii) ushering a new era of network-based medicine, and (iii) bioinspired engineering of physical devices, artificial intelligence, and communication networks. To accomplish this ambitious goal, we established the Center for Network Medicine (CNetMed) – a UCSD-based center that straddles cell, structural, computational, and systems biology, medicine, and engineering.