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X-Ray Structure of a Rex-Family Repressor/NADH Complex Insights into the Mechanism of Redox Sensing

By E Allen Sickmier, Dimitris Brekasis, Shanthi Paranawithana, Jeffrey B Bonanno, Mark S B Paget, Stephen K Burley and Clara L Kielkopf

Abstract

The redox-sensing repressor Rex regulates transcription of respiratory genes in response to the intra cellular NADH/NAD+ redox poise. As a step toward elucidating the molecular mechanism of NADH/NAD+ sensing, the X-ray structure of Thermus aquaticus Rex (T-Rex) bound to effector NADH has been determined at 2.9 Å resolution. The fold of the C-terminal domain of T-Rex is characteristic of NAD(H)-dependent enzymes, whereas the N-terminal domain is similar to a winged helix DNA binding motif. T-Rex dimerization is primarily mediated by ¿domain-swapped¿ a helices. Each NADH molecule binds to the C-terminal domain near the dimer interface. In contrast to NAD(H)-dependent enzymes, the nicotinamide is deeply buried within a hydrophobic pocket that appears to preclude substrate entry. We show that T-Rex binds to the Rex operator, and NADH but not NAD+ inhibits T-Rex/DNA binding activity. A mechanism for redox sensing by Rex family members is proposed by analogy with domain closure of NAD(H)-dependent enzymes

Year: 2005
OAI identifier: oai:sro.sussex.ac.uk:21784
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