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Structures of the Plasmodium falciparum heat-shock protein 70-x ATPase domain in complex with chemical fragments identify conserved and unique binding sites

DOI: 10.1107/S2053230X21007378 DOI Help

Authors: Nada Mohamad (University of Oxford) , Ailsa O'Donoghue (University of Oxford) , Anastassia L. Kantsadi (University of Oxford) , Ioannis Vakonakis (Laboratory of Molecular Biophysics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section F Structural Biology Communications , VOL 77 , PAGES 262 - 268

State: Published (Approved)
Published: August 2021

Open Access Open Access

Abstract: Plasmodium falciparum invades erythrocytes and extensively modifies them in a manner that increases the virulence of this malaria parasite. A single heat-shock 70 kDa-type chaperone, PfHsp70-x, is among the parasite proteins exported to the host cell. PfHsp70-x assists in the formation of a key protein complex that underpins parasite virulence and supports parasite growth during febrile episodes. Previous work resolved the crystallographic structures of the PfHsp70-x ATPase and substrate-binding domains, and showed them to be highly similar to those of their human counterparts. Here, 233 chemical fragments were screened for binding to the PfHsp70-x ATPase domain, resulting in three crystallographic structures of this domain in complex with ligands. Two binding sites were identified, with most ligands binding proximal to the ATPase nucleotide-binding pocket. Although amino acids participating in direct ligand interactions are conserved between the parasite and human erythrocytic chaperones, one nonconserved residue is also present near the ligand. This work suggests that PfHsp70-x features binding sites that may be exploitable by small-molecule ligands towards the specific inhibition of the parasite chaperone.

Journal Keywords: Plasmodium falciparum; PfHsp70-x; heat-shock proteins; malaria; chaperones; erythrocyte remodelling; crystallography; complexes; fragment screening

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 04/08/2021 09:06


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Disease in the Developing World Infectious Diseases Structural biology Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening