Structural Basis of pppGpp Binding to the N-Terminal Domain of the Bifunctional RelA/SpoT Homolog RelSeq: Crystal Structure and MD Analysis

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Abstract
Rel/SpoT family enzymes participate in controlling the cellular levels of the alarmone (p)ppGpp, thereby activating the stringent response and promoting survival under stress conditions. These proteins contain an N-terminal catalytic domain and a C-terminal regulatory domain. They catalyze both the synthesis of ppGpp/pppGpp from ATP and GDP/GTP and their hydrolysis to GDP/GTP and pyrophosphate. Here, we report the crystal structure of the N-terminal domain of Rel from Streptococcus equisimilis (RelSeq385) in complex with pppGpp at 3.2 Å resolution. The asymmetric unit contains a dimer with asymmetric ligation, in which pppGpp occupies only the synthetase site in one monomer, whereas it is observed in both the hydrolase and synthetase sites in the other. Molecular dynamics simulations supported this binding arrangement for the monomer with both sites occupied and revealed additional probable transient binding sites that may contribute to alarmone binding.

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