Dynamics and catalysis in integral membrane pyrophosphatases

Integral membrane pyrophosphatases (mPPases) are novel, conserved ion pumps that use the free energy in the pyrophosphate POP bond to generate a sodium and/or proton motive force. Although not found in multicellular animals, they occur in plants, protozoan parasites (eg malaria: P. falciparum) and (archae)bacteria and are essential under conditions of low-energy stress. mPPase was shown to be essential in P. falciparum (Totanes, unpubl.), and that the mechanism appears to be “binding change” (Li et al, Nat Comm, 2016). However, the most recent work shows that the enzyme is allosteric with half-site reactivity, and allosteric inhibitors have been developed (Vidilaseris et al, Sci Adv, 2019). The model system is T. maritima mPPase (TmPPase). Steered molecular dynamics will be used to derive models of transient states. The work will report on the allosteric changes that are part of our model of dual-pumping and will lead to new designs for inhibitors, covering all the expected timescales (ns-s). This work will have important benefits for understanding allostery in mPPases and so in integral membrane proteins in general. By helping the design of mPPase inhibitors against protozoan parasites (in parallel work), the work will have benefits for animal health, food security and human disease.

Project details

Basic Science

Jun 2023 — Jul 2024

$202,496

United Kingdom