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Royer Lab publishes their first cryoEM structure

Date Posted: Thursday, January 07, 2021

Anne Jecrois, a graduate student carrying out her PhD research jointly in the Royer and Schiffer labs, recently published the first cryoEM structure from either lab.  Her structure of the cancer target protein “CtBP” demonstrates a tetrameric arrangement of subunits in the activated form.  Moreover, in collaboration with the Grossman lab at Virginia Commonwealth University, this paper reports cellular studies providing the first direct evidence that the observed tetrameric form is required for oncogenic activity of CtBP.  Thus, designing inhibitors to disrupt the observed tetrameric arrangement offers promise for eventually developing highly selective antineoplastic agents through structure-based drug design, which is a major goal of Royer’s NIH support (R01 GM119014).

Cryo-EM Structure of CtBP2 Confirms Tetrameric Architecture


cryoEM structureC-terminal binding proteins 1 and 2 (CtBP1 and CtBP2) are transcriptional regulators that activate or repress many genes involved in cellular development, apoptosis and metastasis.  NADH-dependent CtBP activation has been implicated in multiple types of cancer and poor patient prognosis.  Central to understanding activation of CtBP in oncogenesis is uncovering how NADH triggers protein assembly, what level of assembly occurs and if oncogenic activity depends upon such assembly. Here, we present the cryoEM structures of two different constructs of CtBP2 corroborating that the native state of CtBP2 in the presence of NADH is tetrameric. The physiological relevance of the observed tetramer was demonstrated in cell culture showing that CtBP tetramer destabilizing mutants are defective for cell migration, transcriptional repression of E-cadherin and activation of TIAM1. Together with our cryoEM studies, these results highlight the tetramer as the functional oligomeric form of CtBP2. 

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