Assistant Professor LIU Shi
BS in Chemistry, Nankai University, China
MS in Chemistry, The Pennsylvania State University, USA
PhD in Chemistry, University of Wisconsin-Madison, USA
Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore
18 Science Drive 4, Singapore 117543
Tel: +65 6601 3589
Fax: +65 6779 1554
Email: shiliu@nus.edu.sg
As the largest family of transmembrane proteins, G protein-coupled receptors (GPCRs) regulate nearly every aspect of human physiology. Approximately 34% of currently marketed drugs are targeting GPCRs for the treatment of various diseases. On the other hand, more than 100 non-olfactory GPCRs are still considered as orphan receptors for which endogenous ligands and physiological functions remain mysterious. Thus, receptor deorphanization would expand our knowledge on GPCR biology and assist the discovery of more druggable targets from this protein superfamily. By integrating GPCR structural modeling, receptor mutational scanning, and high-throughput screening of ligand library, our lab aims to establish an enabling platform to decipher the signaling mechanisms of orphan GPCRs that are implicated in metabolic regulation. Knowledge gained from the above exploration would help design synthetic ligands with tailored activities or create designer receptors that display customized signaling profiles. These ensuing efforts are expected to generate molecular tools to interrogate the physiological functions of orphan GPCRs and produce molecular modalities with therapeutic potential.
In addition to searching for new therapeutic targets, our group also has a long-standing interest in designing peptidic ligands with novel structures and functions. We are particularly interested in leveraging enzyme catalysis to expand the structural diversity and functional space of peptides. Efforts in this direction involve (i) genome mining and characterization of new biosynthetic enzymes that produce structurally complex peptides (ii) harness the intrinsic recognition promiscuity of wild-type enzymes or design engineered enzymes to process a broad scope of peptide substrates (iii) develop robust biochemical assays or cell-based assays to identify functional peptides with novel mechanisms of action. To facilitate the library construction, we are also interested in supplementing the enzyme catalysis with the state-of-the-art synthetic chemistry research.
Representative Publications:
- Liu, S.; Daley, E. J.; Tran, L.M.L.; Yu, Z.; Reyes, M.; Dean, T.; Khatri, A.; Levine, P.M.; Balana, A.T.; Pratt, M.R.; Jupper, H.; Gellman, S. H; Gardella, T. J. Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants. J. Am. Chem. Soc. 2024, 146, 6522-6529
- Ongpipattanakul, C.# ; Liu, S.# ; Luo, Y. R.# ; Nair, S. K.; van der Donk, W. A. The Mechanism of Thia-Michael Addition Catalyzed by LanC enzymes. Proc. Natl. Acad. Sci. U.S.A. 2023, 120, e2217523120 (Direct Submission, # equal contribution)
- Liu, S.# ; Yu, Z.# ; Daley, E. J.; Bingman, C. A.; Bruchs, A. T.; Gardella, T. J.; Gellman, S. H. Altered Signaling at the PTH Receptor via Modified Agonist Contacts with the Extracellular Domain Provides a Path to Prolonged Agonism In Vivo. Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2212736119 (Direct Submission, # equal contribution)
- Liu, S.; Jean-Alphonse, F. G.; White, A. D.; Wootten, D.; Sexton, P. M.; Gardella, T. J.; Vilardaga, J. P.; Gellman, S. H., Use of Backbone Modification to Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism. J. Am. Chem. Soc. 2019, 141, 14486-14490.
- Liu, S.; Cheloha, R. W.; Watanabe, T.; Gardella, T. J.; Gellman, S. H., Receptor selectivity from minimal backbone modification of a polypeptide agonist. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, 12383-12388. (Direct Submission)
Patent Awarded:
- Analogues of Parathyroid Hormone (1-34) that Function as Agonists of The Parathyroid Hormone Receptor-1 and Display Modified Activity Profiles” Gellman, S.H., Liu, S., Gardella, T.J. US Patent 11780901, 2023