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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. (TetR typically binds tetracycline-Mg complexes inside bacteria, but TetR binding to tetracycline alone has been observed in vitro.)
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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.
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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
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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
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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
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of the TetA operator. 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. Although these residues do not directly contact
56:. In Tc-resistant bacteria, TetA will pump out Tc before it can bind to the ribosome because the repressive action of TetR on TetA is halted by binding of Tc to TetR. Therefore, TetR may have an important role in helping scientists to better understand mechanisms of
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of the target DNA. Binding of TetR to its target DNA sequence causes changes in both the DNA and TetR. TetR causes widening of the major grooves as well as kinking of the DNA; one helix of the HTH motif of TetR adopts a
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Orth P, Schnappinger D, Hillen W, Saenger W, Hinrichs W (March 2000). "Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system".
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282:"Membrane topology of the pBR322 tetracycline resistance protein. TetA-PhoA gene fusions and implications for the mechanism of TetA membrane insertion"
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Werten S, Dalm D, Palm GJ, Grimm CC, Hinrichs W (December 2014). "Tetracycline repressor allostery does not depend on divalent metal recognition".
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TetR (purple and salmon) in complex with its target DNA sequence. HTH motifs are shown in red binding to the major grooves of the DNA. PDB: 1QPI
79:, basal expression of TetR-regulated promoters is low, but expression rises sharply in the presence of even a minute quantity of Tc. The
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TetR. TetR represses the expression of TetA, a membrane protein that pumps out substances toxic to the bacteria like Tc, by binding the
41:(Tc) is a broad family of antibiotics to which bacteria have evolved resistance. Tc normally kills bacteria by binding to the bacterial
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the DNA, they pack against the HTH and this packing is essential for binding. The HTH motifs have mostly hydrophobic interactions with
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Huffman JL, Brennan RG (February 2002). "Prokaryotic transcription regulators: more than just the helix-turn-helix motif".
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Tetracycline-magnesium complex (blue) bound to cavity of TetR (green). HTH motif shown in pink -note conformational change.
91:, where it is often referred to by the name of its tetracycline-resistance phenotype, Tet, not to be confused with TetR.
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TetR as a homodimer: Each monomer is shown in purple or salmon. The helix-turn-helix motif is shown in deep red.
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401:"The role of the N terminus in Tet repressor for tet operator binding determined by a mutational analysis"
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Ramos JL, Martínez-Bueno M, Molina-Henares AJ, Terán W, Watanabe K, Zhang X, et al. (June 2005).
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HTH motif alignment of three TetR family members: MtrR (magenta), SimR (cyan), & AmtR (green)
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and how to treat antibiotic resistant bacteria. TetR is one of many proteins in the TetR
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and halting protein synthesis. The expression of Tc resistance genes is regulated by the
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The DNA-binding domains of TetR recognize a 15 base pair
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helical turn as the result of complex DNA interactions.
31:) are proteins playing an important role in conferring
175:Tetracycline controlled transcriptional activation
399:Berens C, Altschmied L, Hillen W (January 1992).
209:"The TetR family of transcriptional repressors"
71:because of its capacity for fine regulation of
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35:to large categories of bacterial species.
213:Microbiology and Molecular Biology Reviews
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280:Allard JD, Bertrand KP (September 1992).
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83:gene is also present in the widely used
67:TetR is used in artificially engineered
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75:. In the absence of Tc or analogs like
445:Current Opinion in Structural Biology
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482:Regulation of Antibiotic Resistance
405:The Journal of Biological Chemistry
286:The Journal of Biological Chemistry
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111:. Each monomer consists of ten
225:10.1128/mmbr.69.2.326-356.2005
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457:10.1016/S0959-440X(02)00295-6
418:10.1016/S0021-9258(18)46038-3
299:10.1016/S0021-9258(19)37116-9
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358:Nature Structural Biology
497:Tetracycline antibiotics
95:Structure & Function
69:gene regulatory networks
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25:Tet Repressor proteins
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58:antibiotic resistance
33:antibiotic resistance
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129:palindromic sequence
107:TetR functions as a
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148:TetR Protein Family
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39:Tetracycline
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266:2020-08-06
257:"InterPro"
181:References
109:homodimer
73:promoters
47:repressor
491:Category
465:11839496
386:19973826
378:10700280
343:25432019
243:15944459
169:See also
54:operator
43:ribosome
427:1309804
308:1517220
234:1197418
85:E. coli
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89:pBR322
382:S2CID
461:PMID
423:PMID
374:PMID
339:PMID
304:PMID
239:PMID
81:tetA
51:tetA
29:TetR
453:doi
413:doi
409:267
366:doi
331:doi
294:doi
290:267
229:PMC
221:doi
77:ATc
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