| Structural highlights
6ccv is a 11 chain structure with sequence from Mycs2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| NonStd Res: | |
| Gene: | sigA, MSMEG_2758 (MYCS2), rbpA, MSMEG_3858, MSMEI_3768 (MYCS2) |
| Activity: | DNA-directed RNA polymerase, with EC number 2.7.7.6 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[RPOC_MYCS2] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_01322][1] [RBPA_MYCS2] Binds to RNA polymerase (RNAP), probably stimulating transcriptions from principal, but not alternative sigma factor promoters (By similarity). Partially restores transcription in the presence of rifampicin (Rif) in vitro; overexpression leads to an increase in the Rif tolerance in vivo, with smaller colonies. Seems to act by removing Rif from its binding site and preventing its further binding. No longer stimulates transcription in Rif-resistant RNA polymerase (with mutations in rpoB).[2] [3] [RPOB_MYCS2] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit often mutates to generate rifampicin (Rif) resistance. Interaction with RbpA partially restores Rif-inhibited transcription; once the subunit is Rif-resistant however RbpA no longer stimulates transcription.[HAMAP-Rule:MF_01321][4] [RPOA_MYCS2] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_00059][5] [RPOZ_MYCS2] Promotes RNA polymerase assembly. Latches the N- and C-terminal regions of the beta' subunit thereby facilitating its interaction with the beta and alpha subunits.[HAMAP-Rule:MF_00366][6] [A0QW02_MYCS2] Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This sigma factor is the primary sigma factor during exponential growth.[SAAS:SAAS00535554]
Publication Abstract from PubMed
Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif(R)). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant Rif(R) mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif(R) RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.
Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism.,Peek J, Lilic M, Montiel D, Milshteyn A, Woodworth I, Biggins JB, Ternei MA, Calle PY, Danziger M, Warrier T, Saito K, Braffman N, Fay A, Glickman MS, Darst SA, Campbell EA, Brady SF Nat Commun. 2018 Oct 8;9(1):4147. doi: 10.1038/s41467-018-06587-2. PMID:30297823[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dey A, Verma AK, Chatterji D. Role of an RNA polymerase interacting protein, MsRbpA, from Mycobacterium smegmatis in phenotypic tolerance to rifampicin. Microbiology. 2010 Mar;156(Pt 3):873-83. doi: 10.1099/mic.0.033670-0. Epub 2009, Nov 19. PMID:19926651 doi:http://dx.doi.org/10.1099/mic.0.033670-0
- ↑ Dey A, Verma AK, Chatterji D. Role of an RNA polymerase interacting protein, MsRbpA, from Mycobacterium smegmatis in phenotypic tolerance to rifampicin. Microbiology. 2010 Mar;156(Pt 3):873-83. doi: 10.1099/mic.0.033670-0. Epub 2009, Nov 19. PMID:19926651 doi:http://dx.doi.org/10.1099/mic.0.033670-0
- ↑ Dey A, Verma AK, Chatterji D. Molecular insights into the mechanism of phenotypic tolerance to rifampicin conferred on mycobacterial RNA polymerase by MsRbpA. Microbiology. 2011 Jul;157(Pt 7):2056-71. doi: 10.1099/mic.0.047480-0. Epub 2011 , Mar 17. PMID:21415119 doi:http://dx.doi.org/10.1099/mic.0.047480-0
- ↑ Dey A, Verma AK, Chatterji D. Role of an RNA polymerase interacting protein, MsRbpA, from Mycobacterium smegmatis in phenotypic tolerance to rifampicin. Microbiology. 2010 Mar;156(Pt 3):873-83. doi: 10.1099/mic.0.033670-0. Epub 2009, Nov 19. PMID:19926651 doi:http://dx.doi.org/10.1099/mic.0.033670-0
- ↑ Dey A, Verma AK, Chatterji D. Role of an RNA polymerase interacting protein, MsRbpA, from Mycobacterium smegmatis in phenotypic tolerance to rifampicin. Microbiology. 2010 Mar;156(Pt 3):873-83. doi: 10.1099/mic.0.033670-0. Epub 2009, Nov 19. PMID:19926651 doi:http://dx.doi.org/10.1099/mic.0.033670-0
- ↑ Dey A, Verma AK, Chatterji D. Role of an RNA polymerase interacting protein, MsRbpA, from Mycobacterium smegmatis in phenotypic tolerance to rifampicin. Microbiology. 2010 Mar;156(Pt 3):873-83. doi: 10.1099/mic.0.033670-0. Epub 2009, Nov 19. PMID:19926651 doi:http://dx.doi.org/10.1099/mic.0.033670-0
- ↑ Peek J, Lilic M, Montiel D, Milshteyn A, Woodworth I, Biggins JB, Ternei MA, Calle PY, Danziger M, Warrier T, Saito K, Braffman N, Fay A, Glickman MS, Darst SA, Campbell EA, Brady SF. Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism. Nat Commun. 2018 Oct 8;9(1):4147. doi: 10.1038/s41467-018-06587-2. PMID:30297823 doi:http://dx.doi.org/10.1038/s41467-018-06587-2
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