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, 78 (13), 2738-44

Structure of the ATP-binding Domain of Plasmodium Falciparum Hsp90


Structure of the ATP-binding Domain of Plasmodium Falciparum Hsp90

Kevin D Corbett et al. Proteins.


Hsp90 is an important cellular chaperone and attractive target for therapeutics against both cancer and infectious organisms. The Hsp90 protein from the parasite Plasmodium falciparum, the causative agent of malaria, is critical for this organism's survival; the anti-Hsp90 drug geldanamycin is toxic to P. falciparum growth. We have solved the structure of the N-terminal ATP-binding domain of P. falciparum Hsp90, which contains a principal drug-binding pocket, in both apo and ADP-bound states at 2.3 A resolution. The structure shows that P. falciparum Hsp90 is highly similar to human Hsp90, and likely binds agents such as geldanamycin in an identical manner. Our results should aid in the structural understanding of Hsp90-drug interactions in P. falciparum, and provide a scaffold for future drug-discovery efforts.


Figure 1
Figure 1. Overall structure and nucleotide binding by Hsp90N
(A) Close-up of the Hsp90N nucleotide-binding site bound to ADP. Amino acid residues surrounding the active site are shown in stick view, and water molecules involved in hydrogen bonding are shown as spheres. Fo-Fc simulated-annealing omit electron density is shown for ADP and surrounding water molecules, contoured at 6.0 σ. (B) Stereo view of monomer A of Hsp90N, bound to ADP. The protein is colored in a rainbow scheme, with the N-terminus blue and the C-terminus red. Bound ADP is shown in stick view.
Figure 2
Figure 2. Hsp90N comparisons
(A) Superposition of the A (ADP-bound) monomer of Hsp90N (blue; bound ADP in yellow) with the structure of the human Hsp90 N-terminal domain bound to geldanamycin (PDB ID 1YET) (gray; bound geldanamycin not shown). The overall r.m.s.d. of the two domains is 0.79 Å. (B) Superposition of the A (ADP-bound) and B (apo) monomers of Hsp90N. Monomer A is colored blue, and monomer B is colored yellow with the ATP-lid red. The conformation of the ATP-lid in monomer B precludes nucleotide binding, as residues 118–121 would directly overlap with the α- and β-phosphates of ADP.
Figure 3
Figure 3. Prospective drug binding site of PfHsp90
(A) Close-up of the Hsp90N nucleotide- binding site (blue) overlaid with the human Hsp90 N-terminal domain (gray), with residues surrounding the binding pocket show as sticks. The Cα r.m.s.d. for residues displayed is 0.23 Å. (B) Model for geldanamycin binding by PfHsp90, based on structural superposition of Hsp90N with the human Hsp90-geldanamycin complex (above). Geldanamycin and water molecules shown are present in the human Hsp90-geldanamycin complex structure. All chemical groups involved in hydrogen-bonding and Van der Waals interactions with geldanamycin are conserved between human and PfHsp90. (C) 90° rotated view from panel B, showing how Hsp90N residue Asn92 (blue model) clashes with C27 of modeled geldanamycin (yellow sticks, van der Waals surface for this atom is shown as yellow dots). The equivalent residue in human Hsp90, Asn106, is rotated slightly away to accommodate the ligand (gray model, van der Waals surface for the side chain is shown as dots).

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