2MC0: Structural Basis of a Thiopeptide Antibiotic Multidrug Resistance System from Streptomyces lividans:Nosiheptide in Complex with TipAS

Citation:
Abstract
TipA is a transcriptional regulator found in diverse bacteria. It constitutes a minimal autoregulated multidrug resistance system against numerous thiopeptide antibiotics. Here we report the structures of its drug-binding domain TipAS in complexes with promothiocin A and nosiheptide, and a model of the thiostrepton complex. Drug binding induces a large transition from a partially unfolded to a globin-like structure. The structures rationalize the mechanism of promiscuous, yet specific, drug recognition: (i) a four-ring motif present in all known TipA-inducing antibiotics is recognized specifically by conserved TipAS amino acids; and (ii) the variable part of the antibiotic is accommodated within a flexible cleft that rigidifies upon drug binding. Remarkably, the identified four-ring motif is also the major interacting part of the antibiotic with the ribosome. Hence the TipA multidrug resistance mechanism is directed against the same chemical motif that inhibits protein synthesis. The observed identity of chemical motifs responsible for antibiotic function and resistance may be a general principle and could help to better define new leads for antibiotics.
PDB ID: 2MC0Download
MMDB ID: 125322
PDB Deposition Date: 2013/8/12
Updated in MMDB: 2015/12
Experimental Method:
solution nmr
Source Organism:
Similar Structures:
Biological Unit for 2MC0: dimeric; determined by author
Molecular Components in 2MC0
Label Count Molecule
Protein (1 molecule)
1
Hth-type Transcriptional Activator Tipa
Molecule annotation
Nucleotide(1 molecule)
1
Nosiheptide
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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