9G8J
Structure of K+-dependent Na+-PPase from Thermotoga maritima in complex with zoledronate
Summary for 9G8J
| Entry DOI | 10.2210/pdb9g8j/pdb |
| Descriptor | K(+)-stimulated pyrophosphate-energized sodium pump, ZOLEDRONIC ACID, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | inhibitor, complex, enzyme, transporter, membrane protein |
| Biological source | Thermotoga maritima MSB8 |
| Total number of polymer chains | 4 |
| Total formula weight | 314856.42 |
| Authors | Vidilaseris, K.,Liu, J.,Goldman, A. (deposition date: 2024-07-23, release date: 2025-06-04, Last modification date: 2025-11-26) |
| Primary citation | Liu, J.,Shah, A.,Liu, X.,Wort, J.L.,Ma, Y.,Hardman, K.,Johansson, N.G.,Ribeiro, O.,Brookfield, A.,Bowen, A.,Yli-Kauhaluoma, J.,Xhaard, H.,Jeuken, L.J.C.,Goldman, A.,Pliotas, C.,Vidilaseris, K. Conformational dynamics and asymmetry in multimodal inhibition of membrane-bound pyrophosphatases. Elife, 13:-, 2025 Cited by PubMed Abstract: Membrane-bound pyrophosphatases (mPPases) are homodimeric proteins that hydrolyse pyrophosphate and pump H/Na across membranes. They are crucial for the virulence of protist pathogens, making them attractive drug targets. In this study, we investigate the inhibitory effects of seven distinct bisphosphonates against mPPase to explore their mode of action and assist in future small molecule inhibitor development. We solved two structures of mPPase bound to the inhibitors in the enzyme active sites and probed the conformational dynamics of mPPase under multiple inhibitors and functionally relevant conditions by double electron-electron resonance (DEER) spectroscopy. We found that mPPase adopts distinct conformational equilibria in solution in the presence of different inhibitors, including states consistent with asymmetric binding in the active site (closed-open), but a symmetric apo-like conformation on the periplasmic side (open-open). Combined with solid-supported membrane-based electrophysiology recordings, this revealed that during catalysis, one monomer of the dimer remains open, and Na can only be pumped in a closed state. These results further support symmetry-breaking across the membrane, consistent with half-of-the-sites-reactivity. PubMed: 41230777DOI: 10.7554/eLife.102288 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.26 Å) |
Structure validation
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