3AU8

Crystal structure of the ternary complex of an isomerase

Summary for 3AU8

• Entry DOI: 10.2210/pdb3au8/pdb
• Related: 3AU9 3AUA
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: nadph binding, isomerase
• Biological source: Plasmodium falciparum
• Cellular location: Plastid, apicoplast: O96693
• Total number of polymer chains: 2
• Total formula weight: 113259.94

Authors

Umeda, T.,Tanaka, N.,Kusakabe, Y.,Nakanishi, M.,Kitade, Y.,Nakamura, K.T. (deposition date: 2011-02-01, release date: 2011-08-10, Last modification date: 2023-11-01)

Primary citation

Umeda, T.,Tanaka, N.,Kusakabe, Y.,Nakanishi, M.,Kitade, Y.,Nakamura, K.T.
Molecular basis of fosmidomycin's action on the human malaria parasite Plasmodium falciparum
Sci Rep, 1:9-9, 2011

PubMed Abstract: The human malaria parasite Plasmodium falciparum is responsible for the deaths of more than a million people each year. Fosmidomycin has been proven to be efficient in the treatment of P. falciparum malaria by inhibiting 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the non-mevalonate pathway, which is absent in humans. However, the structural details of DXR inhibition by fosmidomycin in P. falciparum are unknown. Here, we report the crystal structures of fosmidomycin-bound complete quaternary complexes of PfDXR. Our study revealed that (i) an intrinsic flexibility of the PfDXR molecule accounts for an induced-fit movement to accommodate the bound inhibitor in the active site and (ii) a cis arrangement of the oxygen atoms of the hydroxamate group of the bound inhibitor is essential for tight binding of the inhibitor to the active site metal. We expect the present structures to be useful guides for the design of more effective antimalarial compounds.

PubMed: 22355528
DOI: 10.1038/srep00009

Experimental method

X-RAY DIFFRACTION (1.86 Å)