6AQU

Crystal Structure of Plasmodium falciparum purine nucleoside phosphorylase: The M183L mutant

Summary for 6AQU

• Entry DOI: 10.2210/pdb6aqu/pdb
• Descriptor: Purine nucleoside phosphorylase, PHOSPHATE ION (3 entities in total)
• Functional Keywords: plasmodium falciparum, purine nucleoside phosphorylase (pnp), pnp mutation, drug resistant pnp., transferase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 54319.42

Authors

Harijan, R.K.,Ducati, R.G.,Namanja-Magliano, H.A.,Bonanno, J.B.,Almo, S.C.,Schramm, V.L. (deposition date: 2017-08-21, release date: 2018-03-28, Last modification date: 2023-10-04)

Primary citation

Ducati, R.G.,Namanja-Magliano, H.A.,Harijan, R.K.,Fajardo, J.E.,Fiser, A.,Daily, J.P.,Schramm, V.L.
Genetic resistance to purine nucleoside phosphorylase inhibition inPlasmodium falciparum.
Proc. Natl. Acad. Sci. U.S.A., 115:2114-2119, 2018

PubMed Abstract: causes the most lethal form of human malaria and is a global health concern. The parasite responds to antimalarial therapies by developing drug resistance. The continuous development of new antimalarials with novel mechanisms of action is a priority for drug combination therapies. The use of transition-state analog inhibitors to block essential steps in purine salvage has been proposed as a new antimalarial approach. Mutations that reduce transition-state analog binding are also expected to reduce the essential catalytic function of the target. We have previously reported that inhibition of host and purine nucleoside phosphorylase (PNP) by DADMe-Immucillin-G (DADMe-ImmG) causes purine starvation and parasite death in vitro and in primate infection models. cultured under incremental DADMe-ImmG drug pressure initially exhibited increased PNP gene copy number and protein expression. At increased drug pressure, additional PNP gene copies appeared with point mutations at catalytic site residues involved in drug binding. Mutant PNPs from resistant clones demonstrated reduced affinity for DADMe-ImmG, but also reduced catalytic efficiency. The catalytic defects were partially overcome by gene amplification in the region expressing PNP. Crystal structures of native and mutated PNPs demonstrate altered catalytic site contacts to DADMe-ImmG. Both point mutations and gene amplification are required to overcome purine starvation induced by DADMe-ImmG. Resistance developed slowly, over 136 generations (2 clonal selection). Transition-state analog inhibitors against PNP are slow to induce resistance and may have promise in malaria therapy.

PubMed: 29440412
DOI: 10.1073/pnas.1525670115

Experimental method

X-RAY DIFFRACTION (2.6 Å)