The structure of the catalytic domain of the ATP synthase from Mycobacterium smegmatis is a target for developing antitubercular drugs

Abstract

The authors declare no conflict of interest.Published under the PNAS license.Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 6FOC).

Structure of mycobacterial ATP synthase with the TB drug bedaquiline

“…In other bacteria (Cingolani and Duncan, 2011;Guo et al, 2019;Shirakihara et al, 2015), subunit e blocks ATP hydrolysis by adopting an inhibitory 'up' conformation where its C-terminal a helix inserts into a catalytic a/b interface. However, as seen previously (Zhang et al, 2019), the purified mycobacterial ATP synthase has only negligible ATP hydrolysis activity ( Fig. 2A, left) even though subunit e adopts a non-inhibitory 'down' conformation (Fig.…”

“…Mycobacterial a subunits possess ~35 residue C-terminal extensions not found in other ATP synthases (Zhang et al, 2019). These extensions were previously proposed to form a helices involved in inhibition (Ragunathan et al, 2017), but this model was questioned because the extensions were not observed in a crystal structure of the F1 region and were predicted to be disordered (Zhang et al, 2019). However, in the present study a single a extension is resolved in the map for each rotational state, forming intimate contacts with the g subunit (Fig.…”

“…The structure of the M. smegmatis F1 region purified in the presence of ADP showed MgADP in both the bTP and bDP sites and a weak density, consistent with phosphate or sulfate, in the bE site (Zhang et al, 2019). This unusual nucleotide occupancy was suggested as an explanation for inhibition of ATP hydrolysis activity (Zhang et al, 2019).…”

“…Instead, the mycobacterial ATP synthase appears to have a unique mechanism for inhibiting ATP hydrolysis (Video 1). Mycobacterial a subunits possess ~35 residue C-terminal extensions not found in other ATP synthases (Zhang et al, 2019). These extensions were previously proposed to form a helices involved in inhibition (Ragunathan et al, 2017), but this model was questioned because the extensions were not observed in a crystal structure of the F1 region and were predicted to be disordered (Zhang et al, 2019).…”

“…2B, red). The remaining two a extensions are not resolved, suggesting that they are disordered when not bound to subunit g. An evolutionarily conserved region of the a extension (Zhang et al, 2019) forms a b strand that creates a parallel b sheet with a b strand from subunit g and possesses multiple charged residues that appear to stabilize this a/g interaction (Fig. 2C).…”