title: Structural and functional basis of transcriptional regulation by TetR family protein CprB from S. coelicolor A3(2).
abstract: Antibiotic production and resistance pathways in Streptomyces are dictated by the interplay of transcriptional regulatory proteins that trigger downstream responses via binding to small diffusible molecules. To decipher the mode of DNA binding and the associated allosteric mechanism in the sub-class of transcription factors that are induced by γ-butyrolactones, we present the crystal structure of CprB in complex with the consensus DNA element to a resolution of 3.25 Å. Binding of the DNA results in the restructuring of the dimeric interface of CprB, inducing a pendulum-like motion of the helix-turn-helix motif that inserts into the major groove. The crystal structure revealed that, CprB is bound to DNA as a dimer of dimers with the mode of binding being analogous to the broad spectrum multidrug transporter protein QacR from the antibiotic resistant strain Staphylococcus aureus. It was demonstrated that the CprB displays a cooperative mode of DNA binding, following a clamp and click model. Experiments performed on a subset of DNA sequences from Streptomyces coelicolor A3(2) suggest that CprB is most likely a pleiotropic regulator. Apart from serving as an autoregulator, it is potentially a part of a network of proteins that modulates the γ-butyrolactone synthesis and antibiotic regulation pathways in S. coelicolor A3(2).
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India IITB-Monash Research Academy, Mumbai 400076, Maharashtra, India.
authors.forename: Hussain
authors.initials: H
authors.lastname: Bhukya
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India.
authors.forename: Ruchika
authors.initials: R
authors.lastname: Bhujbalrao
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India.
authors.forename: Aruna
authors.initials: A
authors.lastname: Bitra
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India ruchi@chem.iitb.ac.in.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Anand
mesh_terms: D001059:Apoproteins / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D016384:Consensus Sequence; D004269:DNA, Bacterial / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D008958:Models, Molecular; D016296:Mutagenesis; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D048372:Streptomyces coelicolor / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001059:Apoproteins; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D014157:Transcription Factors
references.citation: EMBO J. 1988 Feb;7(2):567-72
references.pmid: 2835235
references.citation: Genes Dev. 2010 Nov 15;24(22):2556-65
references.pmid: 21078819
references.citation: Gene. 1998 Nov 5;222(1):133-44
references.pmid: 9813285
references.citation: Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
references.pmid: 9757107
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3773-8
references.pmid: 21321206
references.citation: Nucleic Acids Res. 2012 Feb;40(3):1009-20
references.pmid: 21976733
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Dec;59(Pt 12):2313-5
references.pmid: 14646105
references.citation: EMBO J. 2002 Mar 1;21(5):1210-8
references.pmid: 11867549
references.citation: Nat Struct Biol. 2000 Mar;7(3):215-9
references.pmid: 10700280
references.citation: Microbiol Mol Biol Rev. 2013 Sep;77(3):440-75
references.pmid: 24006471
references.citation: Science. 2001 Dec 7;294(5549):2158-63
references.pmid: 11739955
references.citation: Curr Opin Microbiol. 2006 Jun;9(3):287-94
references.pmid: 16675291
references.citation: Appl Environ Microbiol. 2010 Dec;76(23):7741-53
references.pmid: 20935121
references.citation: Proteins. 2013 Jul;81(7):1166-78
references.pmid: 23408580
references.citation: J Antibiot (Tokyo). 2005 Jan;58(1):1-26
references.pmid: 15813176
references.citation: J Mol Biol. 2011 Apr 22;408(1):40-56
references.pmid: 21354180
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
references.pmid: 21460454
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82
references.pmid: 16369096
references.citation: Appl Environ Microbiol. 2005 Sep;71(9):5050-5
references.pmid: 16151086
references.citation: Microbiol Mol Biol Rev. 2005 Jun;69(2):326-56
references.pmid: 15944459
references.citation: J Bacteriol. 1997 Nov;179(22):6986-93
references.pmid: 9371444
references.citation: Acta Crystallogr D Biol Crystallogr. 2005 Apr;61(Pt 4):449-57
references.pmid: 15805600
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W240-6
references.pmid: 19474339
references.citation: Mol Microbiol. 1998 May;28(4):743-53
references.pmid: 9643542
references.citation: Nucleic Acids Res. 2011 Nov;39(21):9433-47
references.pmid: 21835774
references.citation: Mol Microbiol. 2007 Feb;63(3):838-47
references.pmid: 17181783
references.citation: J Mol Biol. 2004 Feb 13;336(2):409-19
references.pmid: 14757054
references.citation: Chem Rev. 2011 Jan 12;111(1):174-87
references.pmid: 21090718
references.citation: J Mol Biol. 1995 Mar 24;247(2):260-80
references.pmid: 7707374
references.citation: J Biol Chem. 2013 Aug 16;288(33):23687-95
references.pmid: 23803605
references.citation: Mol Microbiol. 1999 Oct;34(1):102-11
references.pmid: 10540289
references.citation: J Bacteriol. 2002 Jun;184(11):3106-13
references.pmid: 12003953
references.citation: Science. 1994 Apr 15;264(5157):418-20
references.pmid: 8153629
references.citation: Mol Microbiol. 2005 Jun;56(5):1373-85
references.pmid: 15882427
references.citation: J Bacteriol. 2001 Dec;183(24):7102-9
references.pmid: 11717268
references.citation: Biosci Biotechnol Biochem. 2005 Mar;69(3):431-9
references.pmid: 15784968
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22263-8
references.pmid: 20080791
references.citation: J Bacteriol. 1995 Nov;177(21):6083-92
references.pmid: 7592371
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references.pmid: 20383002
references.citation: Mol Microbiol. 2002 Aug;45(3):735-44
references.pmid: 12139619
references.citation: Dokl Akad Nauk SSSR. 1967 Nov-Dec;177(1):232-5
references.pmid: 5622968
references.citation: J Bacteriol. 1998 Jul;180(13):3317-22
references.pmid: 9642182
references.citation: Science. 2006 Feb 24;311(5764):1113-6
references.pmid: 16497924
references.citation: Front Biosci. 2002 Oct 01;7:d2045-57
references.pmid: 12165483
references.citation: Z Allg Mikrobiol. 1973;13(8):647-55
references.pmid: 4131140
references.citation: Proc Natl Acad Sci U S A. 1980 Jul;77(7):3974-7
references.pmid: 7001450
references.citation: Mol Microbiol. 2011 Oct;82(1):236-50
references.pmid: 21883525
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10586-91
references.pmid: 23754405
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):271-81
references.pmid: 21460445
references.citation: J Biol Chem. 2010 Aug 27;285(35):27440-27448
references.pmid: 20562102
references.citation: EMBO J. 2011 Jan 5;30(1):154-64
references.pmid: 21113127
references.citation: Gene. 1983 Aug;23(2):149-56
references.pmid: 6311683
references.citation: FEBS Lett. 1991 May 6;282(2):415-8
references.pmid: 1645287
references.citation: Mol Microbiol. 2005 Apr;56(2):465-79
references.pmid: 15813737
references.citation: Nat Struct Mol Biol. 2010 Aug;17(8):971-5
references.pmid: 20639888
references.citation: Biochemistry. 2006 Jun 20;45(24):7429-33
references.pmid: 16768438
references.citation: J Bacteriol. 1999 Aug;181(16):5081-4
references.pmid: 10438782
references.citation: Arch Microbiol. 2007 Nov;188(5):541-6
references.pmid: 17611737
references.citation: Nat Rev Microbiol. 2006 Dec;4(12):887-99
references.pmid: 17109029
references.citation: Mol Microbiol. 1997 Jun;24(5):991-1000
references.pmid: 9220006
references.citation: J Bacteriol. 2002 Apr;184(8):2324-30
references.pmid: 11914368
references.citation: J Mol Biol. 2008 Nov 21;383(4):753-61
references.pmid: 18804114
references.citation: J Mol Biol. 2010 Oct 22;403(2):174-84
references.pmid: 20691702
references.citation: Mol Microbiol. 2007 Nov;66(3):622-32
references.pmid: 17877713
references.citation: Mol Microbiol. 2001 Sep;41(5):1015-28
references.pmid: 11555283
references.citation: J Mol Biol. 2007 Jul 20;370(4):609-19
references.pmid: 17543986
references.citation: Cell. 2006 Apr 21;125(2):237-46
references.pmid: 16630813
references.citation: Microbiol Mol Biol Rev. 2013 Mar;77(1):112-43
references.pmid: 23471619
references.citation: Antioxid Redox Signal. 2010 Jan;12(1):53-91
references.pmid: 19634988