Structure of the mycobacterial ATP synthase F
            <sub>o</sub>
            rotor ring in complex with the anti-TB drug bedaquiline

Preiß, Laura; Langer, Julian D.; Yıldız, Özkan; Eckhardt-Strelau, Luise; Guillemont, Jérôme; Koul, Anil; Meier, Thomas

doi:10.1126/sciadv.1500106

Cited by 247 publications

(319 citation statements)

References 51 publications

(88 reference statements)

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“…Vertebrate and probably all metazoan ATP synthases have c 8 -rings (21). Fungal ATP synthases contain c 10 -rings (20), various eubacterial enzymes have rings of c 9 , c 11 , c 12 , c 13 , and c 15 (22)(23)(24)(25)(26)(27)(28), and the enzyme from spinach chloroplasts has a c 14 -ring (29). The turning of the rotor carries energy from the transmembrane proton-motive force generated by oxidative metabolism or photosynthesis to the catalytic domain, to energize the phosphorylation of ADP.…”

mentioning

confidence: 99%

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

Duncan

Robinson

Walker

2016

Proc. Natl. Acad. Sci. U.S.A.

126

132

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The anionic lipid cardiolipin is an essential component of active ATP synthases. In metazoans, their rotors contain a ring of eight c-subunits consisting of inner and outer circles of N-and C-terminal α-helices, respectively. The beginning of the C-terminal α-helix contains a strictly conserved and fully trimethylated lysine residue in the lipid headgroup region of the membrane. Larger rings of known structure, from c 9 -c 15 in eubacteria and chloroplasts, conserve either a lysine or an arginine residue in the equivalent position. In computer simulations of hydrated membranes containing trimethylated or unmethylated bovine c 8 -rings and bacterial c 10 -or c 11 -rings, the head-groups of cardiolipin molecules became associated selectively with these modified and unmodified lysine residues and with adjacent polar amino acids and with a second conserved lysine on the opposite side of the membrane, whereas phosphatidyl lipids were attracted little to these sites. However, the residence times of cardiolipin molecules with the ring were brief and sufficient for the rotor to turn only a fraction of a degree in the active enzyme. With the demethylated c 8 -ring and with c 10 -and c 11 -rings, the density of bound cardiolipin molecules at this site increased, but residence times were not changed greatly. These highly specific but brief interactions with the rotating c-ring are consistent with functional roles for cardiolipin in stabilizing and lubricating the rotor, and, by interacting with the enzyme at the inlet and exit of the transmembrane proton channel, in participation in proton translocation through the membrane domain of the enzyme.ardiolipin is associated uniquely with energy-transducing membranes in mitochondria and eubacteria. In mitochondria, it is found in the inner membrane and is synthesized close to, or in, the inner leaflet (1) where most of it remains (2, 3). Cardiolipin consists of two 3-phosphatidyl groups linked by a glycerol bridge, and in bovine mitochondria, the four acyl chains have 18 carbon atoms with one or two unsaturated linkages (4). It has been proposed that under physiological conditions, the central hydroxyl and the two phosphates trap a proton in a resonance structure and that cardiolipin carries one net negative charge (5). However, re-evaluations of the pK a values of the phosphates indicate that under physiological conditions, the head-group of cardiolipin bears two negative charges (6, 7).Cardiolipin and other phospholipids are essential components of active ATP synthases isolated from mitochondria (8-12). It has been suggested that cardiolipin acts to stabilize and lubricate the rotating c-ring (13) or to aid in proton transfer (5), but it is not known where or how cardiolipin binds to the enzyme. Excluding the regulatory protein IF 1, the bovine ATP synthase complex is built from 28 polypeptide chains of 16 varieties (14). About 85% of a mosaic overall structure has been determined to atomic resolution by structural analysis of constituent domains (15-18), and an intact enzyme ...

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mentioning

confidence: 99%

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

Duncan

Robinson

Walker

2016

Proc. Natl. Acad. Sci. U.S.A.

126

132

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“…Homology modeling of MTB ac9 protein complex: A high resolution X-ray diffraction structure of rotor complex in M. phlei with c9 configuration (PDB ID: 4V1G; resolution: 1.55 Å) and the same protein with co-crystallized bedaquiline (PDB ID: 4V1F; resolution: 1.7 Å) (http://www.rcsb.org/pdb/) has been solved by Preiss et al [15]. The structure is invaluable in understanding the binding mode of bedaquiline and M. phlei shares an impressive 90 % sequence identity with pathogenic bacterium's rotor sequence.…”

Section: Methodsmentioning

confidence: 99%

in silico Quest Guided by Physico-Chemical Descriptors of Bedaquiline for New Scaffolds with Potential Inhibitory Capacity against Homology Model of Mycobacterium F1F0 ATP Synthase

Munnaluri¹,

Manga²

2018

Asian J. Chem.

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As the first US FDA approved drug for treating pulmonary multi drug resistant tuberculosis (MDR-TB) in the last 40 years, bedaquiline (TMC207, Sirturo TM ) stands out as cynosure in the circles of synthetic chemists exploring new therapeutics against tuberculosis. The remarkable efficacy of bedaquiline in treating tuberuculosis lies in its ability to target the energy metabolism that affects both replicating as well as dormant forms of M. tuberculosis (MTB). Despite its promising antitubercular profile, bedaquiline raises serious concern with its string of side effects and emergence of resistant strains, warrants a quest for better substitutes. In the present work, we employed in silico methods like homology modeling and virtual screening to zero in on molecules that exhibit high affinity at the binding site of bedaquiline.

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“…Just such an antibiotic has been shown to act by binding to the c-ring and inhibiting its rotation. 67 In summary, there is transport of H + down a concentration gradient across the membrane through the ATP synthase. This transport is coupled through the structure of the ATP synthase to the phosphorylation of ADP to make ATP.…”

Section: Atp Synthasementioning

confidence: 99%

Membrane Transport

Yèagle

2016

The Membranes of Cells

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Structure of the mycobacterial ATP synthase F _o rotor ring in complex with the anti-TB drug bedaquiline

Abstract: Structure and inhibition mechanism of the anti-TB drug bedaquiline bound to the ATP synthase rotor from Mycobacteria.

Cited by 247 publications

References 51 publications

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

in silico Quest Guided by Physico-Chemical Descriptors of Bedaquiline for New Scaffolds with Potential Inhibitory Capacity against Homology Model of Mycobacterium F1F0 ATP Synthase

Membrane Transport

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Structure of the mycobacterial ATP synthase F o rotor ring in complex with the anti-TB drug bedaquiline

Abstract: Structure and inhibition mechanism of the anti-TB drug bedaquiline bound to the ATP synthase rotor from Mycobacteria.

Cited by 247 publications

References 51 publications

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases

in silico Quest Guided by Physico-Chemical Descriptors of Bedaquiline for New Scaffolds with Potential Inhibitory Capacity against Homology Model of Mycobacterium F1F0 ATP Synthase

Membrane Transport

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Structure of the mycobacterial ATP synthase F _o rotor ring in complex with the anti-TB drug bedaquiline