报告推荐 | Ronald J Quinn《Natural Product – Protein Interactions》

Asian Symposium on Medicinal Plants and Spices XVII (2021) - Virtual Conference （ASOMPS XVII） 将于 2021年8月18-19日在线上举办。本次会议主题为“Contextualising Natural Product Science for Societal Relevance”。作为本次会议的演讲嘉宾之一，Ronald J Quinn教授在此与您分享他的报告内容，并诚邀您与会。

Natural Product – Protein Interactions

Ronald J Quinn

Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia

Correspondence: r.quinn@griffith.edu.au

Abstract:

Native Mass Spectrometry using an electrospray ionization Fourier transform ion cyclotron resonance mass spectrometer (ESI-FTICR-MS) can detect protein in its native folded state and can detect and distinguish non-covalent and covalent protein-ligand complexes. Native Mass Spectrometry allows an unparalleled ability to observe complexes between natural products and their protein targets. 

These experiments can be applied to discovery of bioactive natural products and the identification of the target of a bioactive natural product where the interaction is a binary complex.

(i) A single protein can be interrogated with natural product libraries to find selective ligands against a protein of interest. (Target-based Screening).

(ii) A compound with phenotypic activity can be interrogated against a panel of putative validated protein targets (PhenoTarget Screening). We illustrate the concept of PhenoTarget screening using a cell-based phenotypic assay against Mycobacterium tuberculosis coupled to target identification using native mass spectrometry.

(iii) A compound can be a bait to pull out a target from a cell lysate (Target Identification)

Ternary complexes can be observed between a protein and two natural products and between a modified natural product and two proteins.

(i) Fragment-sized natural products can bind to two sites in a larger protein cavity (Fragment-based Hit Elaboration). We have reported 96 low molecular weight natural products identified as binding partners of 32 putative malarial targets.

(ii) One compound could bind to an active site and one compound could bind toan allosteric site.

(iii) A ligand (PROTAC) can bind to two proteins. The ability to see both the binary complex between a protein of interest and a PROTAC molecule and the binary complex between an E3 ligase can be used to design new PROTAC molecules. Several natural products have been designed into PROTACs.

Reference：

Sternicki, L. M.; Nonomiya, J.; Liu, M.; Mulvihill, M.M.; Quinn, R. J., Native mass spectrometry for the study of PROTACGNE‐987‐containing ternary complexes. ChemMedChem 2021, doi:10.1002/cmdc.202100113.

Liu, M.; Van Voorhis, W.C.; Quinn, R. J., Development of a target identification approach using nativemass spectrometry. Sci Rep 2021, 11 (1), 2387-12.

Xie, Y.; Feng, Y.; DiCapua, A.; Mak, T.; Buchko, G. W.; Myler, P. J.; Liu, M.; Quinn, R. J., Aphenotarget approach for identifying an alkaloid interacting with the tuberculosis protein Rv1466. Mar. Drugs 2020, 18 (3), 149.

Keywords:

Ligand-protein, native Mass spectrometry, Target ID, PROTAC