2gdi

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Crystal structure of thiamine pyrophosphate-specific riboswitch in complex with thiamine pyrophosphate

Overview

Riboswitches are metabolite-sensing RNAs, typically located in the, non-coding portions of messenger RNAs, that control the synthesis of, metabolite-related proteins. Here we describe a 2.05 angstroms crystal, structure of a riboswitch domain from the Escherichia coli thiM mRNA that, responds to the coenzyme thiamine pyrophosphate (TPP). TPP is an active, form of vitamin B1, an essential participant in many protein-catalysed, reactions. Organisms from all three domains of life, including bacteria, plants and fungi, use TPP-sensing riboswitches to control genes, responsible for importing or synthesizing thiamine and its phosphorylated, derivatives, making this riboswitch class the most widely distributed, member of the metabolite-sensing RNA regulatory system. The structure, reveals a complex folded RNA in which one subdomain forms an intercalation, pocket for the 4-amino-5-hydroxymethyl-2-methylpyrimidine moiety of TPP, whereas another subdomain forms a wider pocket that uses bivalent metal, ions and water molecules to make bridging contacts to the pyrophosphate, moiety of the ligand. The two pockets are positioned to function as a, molecular measuring device that recognizes TPP in an extended, conformation. The central thiazole moiety is not recognized by the RNA, which explains why the antimicrobial compound pyrithiamine pyrophosphate, targets this riboswitch and downregulates the expression of thiamine, metabolic genes. Both the natural ligand and its drug-like analogue, stabilize secondary and tertiary structure elements that are harnessed by, the riboswitch to modulate the synthesis of the proteins coded by the, mRNA. In addition, this structure provides insight into how folded RNAs, can form precision binding pockets that rival those formed by protein, genetic factors.

About this Structure

2GDI is a Protein complex structure of sequences from [1] with , , and as ligands. Full crystallographic information is available from OCA.

Reference

Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch., Serganov A, Polonskaia A, Phan AT, Breaker RR, Patel DJ, Nature. 2006 Jun 29;441(7097):1167-71. Epub 2006 May 21. PMID:16728979

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