Time and Date：2:00pm, Oct. 23, 2014
Address：Auditorium, A109, Haike Rd. Campus
Reporter：Prof. Dinshaw J. Patel
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065
Title: Structure-Function Studies of Cytosolic DNA Sensors Governing the Interferon Response
Host: Ming Lei, Researcher
Welcome to attend！
Structure-Function Studies of Cytosolic DNA Sensors Governing the Interferon Response
Dinshaw J. Patel, Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065
The lecture will outline recent results that have emerged from a collaborative program (1) on the metazoan cytoplasmic dsDNA sensor cyclic GMP-AMP synthase (cGAS). These studies address the role of cyclic GMP-AMP (cGAMP) as a metazoan second messenger triggering an interferon response, with the cGAMP linkage isomer c[G(2’,5’)pA(3’,5’)p] generated from GTP and ATP by DNA-activated cGAS. Our structural-functional studies will highlight how a single catalytic pocket can generate c[G(2’,5’)pA(3’,5’)p] through a step-wise cyclization process, thereby identifying and structurally/chemically characterizing a founding member of a new family of metazoan cyclic hetero dinucleotide second messengers (2). The lecture will also outline structure-function studies of the activation of signaling protein STING (stimulator of interferon genes) by c[G(2’,5’)pA(3’,5’)p], its linkage isomers and drug DMXAA (3, 4).
(1) Laboratories of Thomas Tuschl (Rockefeller University, in vitro biochemical studies), Winfried Barchet and Gunther Hartmann (University Hospital, Bonn, in vivo cellular studies), Liang Deng (Memorial Sloan-Kettering Cancer Center, innate signaling mechanisms), Roger Jones (Rutgers University, synthetic chemistry) and our group (Memorial Sloan-Kettering Cancer Center, structural biology).
(2) Gao, P. et al. and Patel, D. J. (2013). Cyclic [G(2’,5’)pA(3’,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094-1107.
(3) Gao, P. et al. and Patel, D.J. (2013) Structure-function analysis of STING activation by c[G(2’,5’)pA(3’,5’)p] and targeting by DMXAA. Cell 154, 748-762.
(4) Gao, P. et al. and Patel, D. J. (2014). Binding pocket and lid region substituents render human STING sensitive to mouse-selective drug DMXAA. Cell Reports 8, 1668-1676.