TetR

File:TetR --TcMg- complex (2).png

TetR functions as a homodimer. Each monomer consists of ten alpha helices connected by loops and turns. The overall structure of TetR can be broken down into two DNA-binding domains (one per monomer) and a regulatory core, which is responsible for tetracycline recognition and dimerization. TetR dimerizes by making hydrophobic contacts within the regulatory core. There is a binding cavity for tetracycline in the outer helices of the regulatory domain. When tetracycline binds this cavity, it causes a conformational change that affects the DNA-binding domain so that TetR is no longer able to bind DNA. As a result, TetA and TetR are expressed. There is still some debate in the field whether tetracycline derivatives alone can cause this conformational change or whether tetracycline must be in complex with magnesium to bind TetR.{{Cite journal |vauthors=Werten S, Dalm D, Palm GJ, Grimm CC, Hinrichs W |date=December 2014 |title=Tetracycline repressor allostery does not depend on divalent metal recognition |journal=Biochemistry |volume=53 |issue=50 |pages=7990–8 |doi=10.1021/bi5012805 |pmid=25432019}} (TetR typically binds tetracycline-Mg²⁺ complexes inside bacteria, but TetR binding to tetracycline alone has been observed in vitro.){{cn|date=March 2023}}

File:TetR-DNAcomplex (2).png

The DNA-binding domains of TetR recognize a 15 base pair palindromic sequence of the TetA operator.{{Cite journal |vauthors=Orth P, Schnappinger D, Hillen W, Saenger W, Hinrichs W |date=March 2000 |title=Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system |journal=Nature Structural Biology |volume=7 |issue=3 |pages=215–9 |doi=10.1038/73324 |pmid=10700280 |s2cid=19973826}} These domains mainly consist of a helix-turn-helix (HTH) motif that is common in TetR protein family members (see below). However, the N-terminal residues preceding this motif have also been shown to be important for DNA binding.{{Cite journal |vauthors=Berens C, Altschmied L, Hillen W |date=January 1992 |title=The role of the N terminus in Tet repressor for tet operator binding determined by a mutational analysis |url=http://www.jbc.org/content/267/3/1945 |journal=The Journal of Biological Chemistry |volume=267 |issue=3 |pages=1945–52 |doi=10.1016/S0021-9258(18)46038-3 |pmid=1309804 |doi-access=free}} Although these residues do not directly contact the DNA, they pack against the HTH and this packing is essential for binding. The HTH motifs have mostly hydrophobic interactions with major grooves of the target DNA. Binding of TetR to its target DNA sequence causes changes in both the DNA and TetR.{{Cite journal |vauthors=Huffman JL, Brennan RG |date=February 2002 |title=Prokaryotic transcription regulators: more than just the helix-turn-helix motif |journal=Current Opinion in Structural Biology |volume=12 |issue=1 |pages=98–106 |doi=10.1016/S0959-440X(02)00295-6 |pmid=11839496}} TetR causes widening of the major grooves as well as kinking of the DNA; one helix of the HTH motif of TetR adopts a 3₁₀ helical turn as the result of complex DNA interactions.{{cn|date=March 2023}}

File:HTH alignment of 3 TetR family members.png

As of June 2005, this family of proteins had about 2,353 members that are transcriptional regulators. (Transcriptional regulators control gene expression.) These proteins contain a helix-turn-helix (HTH) motif that is the DNA-binding domain. The second helix is considered to be most important for DNA sequence specificity and often recognizes nucleic acids within the major groove of the double helix. In the majority of the family members, this motif is on the N-terminal end of the protein and is highly conserved. The high conservation of the HTH motif is not observed for the other domains of the protein. The differences observed in these other regulatory domains are likely due to differences in the molecules that each family member senses.{{cn|date=March 2023}}

TetR protein family members are mostly transcriptional repressors, meaning that they prevent the expression of certain genes at the DNA level. These proteins can act on genes with various functions including antibiotic resistance, biosynthesis and metabolism, bacterial pathogenesis, and response to cell stress.{{cn|date=March 2023}}

• Tetracycline controlled transcriptional activation

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{{Reflist}}

• [https://archive.today/20121210214418/https://www.bio.cmu.edu/courses/03441/TermPapers/2000TermPapers/group2/resi-reg.html Regulation of Antibiotic Resistance]

Category:Tetracycline antibiotics