1. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
2. These authors contributed equally to this work.

Correspondence to: Alexander Serganov^1,2Dinshaw J. Patel¹ Correspondence and requests for materials should be addressed to A.S. (Email: serganoa@mskcc.org) or D.J.P. (Email: pateld@mskcc.org).

In bacteria, the intracellular concentration of several amino acids is controlled by riboswitches^{1, 2, 3, 4}. One of the important regulatory circuits involves lysine-specific riboswitches, which direct the biosynthesis and transport of lysine and precursors common for lysine and other amino acids^{1, 2, 3}. To understand the molecular basis of amino acid recognition by riboswitches, here we present the crystal structure of the 174-nucleotide sensing domain of the Thermotoga maritima lysine riboswitch in the lysine-bound (1.9 ångström (Å)) and free (3.1 Å) states. The riboswitch features an unusual and intricate architecture, involving three-helical and two-helical bundles connected by a compact five-helical junction and stabilized by various long-range tertiary interactions. Lysine interacts with the junctional core of the riboswitch and is specifically recognized through shape-complementarity within the elongated binding pocket and through several direct and K⁺-mediated hydrogen bonds to its charged ends. Our structural and biochemical studies indicate preformation of the riboswitch scaffold and identify conformational changes associated with the formation of a stable lysine-bound state, which prevents alternative folding of the riboswitch and facilitates formation of downstream regulatory elements. We have also determined several structures of the riboswitch bound to different lysine analogues⁵, including antibiotics, in an effort to understand the ligand-binding capabilities of the lysine riboswitch and understand the nature of antibiotic resistance. Our results provide insights into a mechanism of lysine-riboswitch-dependent gene control at the molecular level, thereby contributing to continuing efforts at exploration of the pharmaceutical and biotechnological potential of riboswitches.

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