Exchange proteins directly activated by cAMP (EPACs) are important allosteric regulators of cAMP-mediated signal\r\ntransduction pathways. To understand the molecular mechanism of EPAC activation, we have combined site-directed\r\nmutagenesis, X-ray crystallography, and peptide amide hydrogen/deuterium exchange mass spectrometry (DXMS) to probe\r\nthe structural and conformational dynamics of EPAC2-F435G, a constitutively active EPAC2 mutant. Our study demonstrates\r\nthat conformational dynamics plays a critical role in cAMP-induced EPAC activation. A glycine mutation at 435 position\r\nshifts the equilibrium of conformational dynamics towards the extended active conformation.
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