Molecular Basis for the Specific Recognition of the Metazoan Cyclic GMP-AMP by the Innate Immune Adaptor Protein STING

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Jul 8

PMID 26150511

Citations 31

Authors

Heping Shi

Jiaxi Wu

Zhijian J Chen

Chuo Chen

Affiliations

Soon will be listed here.

Abstract

Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2'3'-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2'3'-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. Here we show that 2'3'-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein-ligand interactions.

Citing Articles

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Animal and bacterial viruses share conserved mechanisms of immune evasion.

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