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Nucleic Acids Res. 2018 Jan 9;46(1):403-420. doi: 10.1093/nar/gkx1148.

Novel structural features drive DNA binding properties of Cmr, a CRP family protein in TB complex mycobacteria.

Author information

1
Department of Biomedical Sciences, School of Public Health, University at Albany, SUNY, Albany, NY 12201, USA.
2
New York Structural Biology Center, New York, NY 10027, USA.
3
Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, PO Box 22002, Albany, NY 12201-2002, USA.

Abstract

Mycobacterium tuberculosis (Mtb) encodes two CRP/FNR family transcription factors (TF) that contribute to virulence, Cmr (Rv1675c) and CRPMt (Rv3676). Prior studies identified distinct chromosomal binding profiles for each TF despite their recognizing overlapping DNA motifs. The present study shows that Cmr binding specificity is determined by discriminator nucleotides at motif positions 4 and 13. X-ray crystallography and targeted mutational analyses identified an arginine-rich loop that expands Cmr's DNA interactions beyond the classical helix-turn-helix contacts common to all CRP/FNR family members and facilitates binding to imperfect DNA sequences. Cmr binding to DNA results in a pronounced asymmetric bending of the DNA and its high level of cooperativity is consistent with DNA-facilitated dimerization. A unique N-terminal extension inserts between the DNA binding and dimerization domains, partially occluding the site where the canonical cAMP binding pocket is found. However, an unstructured region of this N-terminus may help modulate Cmr activity in response to cellular signals. Cmr's multiple levels of DNA interaction likely enhance its ability to integrate diverse gene regulatory signals, while its novel structural features establish Cmr as an atypical CRP/FNR family member.

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