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.

Short chain dehydrogenases/reductases (SDR) constitute a large protein family. The SDR family now includes more than 1,000 enzymes from humans, mammals, insects and bacteria, and exhibits a wide variety of substrate specificity for steroids, retinoids, prostaglandins, sugars, alcohols and other small molecules. These enzymes have a residue identity level of 15-30 perent. Much has been done in the last decade to understand the structure function relationships in the SDR enzymes. This review summarizes recent progress of structural and functional studies of the enzymes belonging to the SDR family (X ray crystal structure analyses and site directed mutagenesis studies). Based on these studies, the three dimensional structure, catalytic mechanism, coenzyme specificity, and substrate specificity of the SDR enzymes are discussed.

An interferon‐induced endoribonuclease, ribonuclease L (RNase L), is implicated in both the molecular mechanism of action of interferon and the fundamental control of RNA stability in mammalian cells. RNase L is catalytically active only after binding to an unusual activator molecule containing a 5′‐phosphorylated 2′,5′‐linked oligoadenylate (2‐5A), in the N‐terminal half. Here, we report the crystal structure of the N‐terminal ankyrin repeat domain (ANK) of human RNase L complexed with the activator 2‐5A. This is the first structural view of an ankyrin repeat structure directly interacting with a nucleic acid, rather than with a protein. The ANK domain folds into eight ankyrin repeat elements and forms an extended curved structure with a concave surface. The 2‐5A molecule is accommodated at a concave site and directly interacts with ankyrin repeats 2–4. Interestingly, two structurally equivalent 2‐5A binding motifs are found at repeats 2 and 4. The structural basis for 2‐5A recognition by ANK is essential for designing stable 2‐5As with a high likelihood of activating RNase L.

The specific aminoacylation of tRNA by tyrosyl-tRNA synthetases (TyrRSs) relies on the identity determinants in the cognate tRNA^Tyrs. We have determined the crystal structure of Saccharomyces cerevisiae TyrRS (SceTyrRS) complexed with a Tyr-AMP analog and the native tRNA^Tyr(GΨA). Structural information for TyrRS–tRNA^Tyr complexes is now full-line for three kingdoms. Because the archaeal/eukaryotic TyrRSs–tRNA^Tyrs pairs do not cross-react with their bacterial counterparts, the recognition modes of the identity determinants by the archaeal/eukaryotic TyrRSs were expected to be similar to each other but different from that by the bacterial TyrRSs. Interestingly, however, the tRNA^Tyr recognition modes of SceTyrRS have both similarities and differences compared with those in the archaeal TyrRS: the recognition of the C1-G72 base pair by SceTyrRS is similar to that by the archaeal TyrRS, whereas the recognition of the A73 by SceTyrRS is different from that by the archaeal TyrRS but similar to that by the bacterial TyrRS. Thus, the lack of cross-reactivity between archaeal/eukaryotic and bacterial TyrRS-tRNA^Tyr pairs most probably lies in the different sequence of the last base pair of the acceptor stem (C1-G72 vs G1-C72) of tRNA^Tyr. On the other hand, the recognition mode of Tyr-AMP is conserved among the TyrRSs from the three kingdoms.