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Fasciculata at 2.4-A Resolution (Glutathione Reductase/Oxidative Stress/Trypanosomiasls/Protein Crystaoraphy/Drug Design) JOHN KURIYAN*T, XIANG-PENG Kongt, T

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Fasciculata at 2.4-A Resolution (Glutathione Reductase/Oxidative Stress/Trypanosomiasls/Protein Crystaoraphy/Drug Design) JOHN KURIYAN*T, XIANG-PENG Kongt, T Proc. Nati. Acad. Sci. USA Vol. 88, pp. 8764-8768, October 1991 Biochemistry X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution (glutathione reductase/oxidative stress/trypanosomiasls/protein crystaoraphy/drug design) JOHN KURIYAN*t, XIANG-PENG KONGt, T. S. R. KRISHNA*t, ROBERT M. SWEETt, NICHOLAS J. MURGOLO§, HELEN FIELD§, ANTHONY CERAMI§, AND GRAEME B. HENDERSON§¶ *Howard Hughes Medical Institute and tLaboratory of Molecular Biophysics, and §Laboratory of Medical Biochemistry, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and tDepartment of Biology, Brookhaven National Laboratory, Upton, NY 11973 Communicated by Martin Karplus, July 5, 1991 ABSTRACT Trypanosomes and related protozoan para- promising target for the development ofinhibitors that do not sites lack glutathione reductase and possess instead a closely react with the host enzyme. related enzyme that serves as the reductant of a bis(glu- Insight into the basis of substrate discrimination in these tathione)-spermidine conjugate, trypanothione. The human enzymes has been obtained by studies on the reduction by TR and parasite enzymes have mutually exclusive substrate spec- of T(S)2 analogs (7) and by site-directed mutagenesis and ificities, providing a route for the design of therapeutic agents molecular modeling of TR and GR (10-13). These studies by specific inhibition of the parasite enzyme. We report here have been aided greatly by the x-ray structures of GR (at the three-dimensional structure of trypanothione reductase 1.54-A resolution) and GR complexed with NADPH and from Crithidiafasciculata and show that it closely resembles the GSSG (at 2-A resolution) that have been determined by structure of human glutathione reductase. In particular, the Schulz and coworkers (4, 14, 15). However, a complete core structure surrounding the catalytic machiney is almost understanding of the molecular basis for the altered speci- identical in the two enzymes. However, significant differences ficities of the human and parasite enzymes requires direct are found at the substrate binding sites. A cluster of basic structural information for the latter. We present here the residues in glutathione reductase is replaced by neutral, hy- x-ray structure of TR from C. fasciculata (16) at 2.4- drophobic, or acidic residues in trypanothione reductase, resolution in the absence of T(S)2. 11 consistent with the nature of the spermidine linkage and the change in overall charge of the substrate from -2 to +1, METHODS respectively. The binding site is more open in trypanothione TR was purified as described (5) but with the incorporation reductase due to rotations ofabout 4° in the domains that form of an additional ion-exchange chromatography step the site, with relative shifts of as much as 2-3 A in residue (Mono-Q, Pharmacia) that resulted in the separation of three positions. These results provide a detailed view of the residues closely spaced peaks containing TR activity. All three peaks that can interact with potential inhibitors and complement yield similar well-ordered crystals (16). Characterization of previous modeling and mutagenesis studies on the two en- these crystals revealed a slightly different crystal form which zymes. was used for the structure determination (form III, P21, a = 60.0 A, b = 161.8 A, c = 61.5 A, p = 104.1°, dimer in the A promising route toward finding improved therapeutic asymmetric unit). Data collection was carried out at station agents for diseases caused by trypanosomes and leishmanias X12-C of the National Synchrotron Light Source at is to identify differences between the metabolism of the Brookhaven, using a FAST area detector (Enraf-Nonius, parasite and the host and to develop inhibitors of enzymes Delft, The Netherlands), with x-rays of 1.1-A wavelength. specific to the parasite (1, 2). Trypanosomes and leishmanias Intensities were accumulated over 0.10 rotations, using ex- do not possess the flavoenzyme glutathione reductase (GR), posure times ranging from 10 to 20 sec. Strong diffraction was which is found in most aerobic organisms and catalyzes the observed to 2-A resolution. We merged 131,449 measure- reduction by NADPH ofoxidized glutathione (GSSG) to two ments of 42,201 unique reflections to 2-A resolution with an molecules of -glutamylcysteinylglycine (-Glu-Cys-Gly) (2, overall error [Rsym(I)] of0.079o (17, 18). The final data set is 3). These parasites rely instead on a bis(glutathione)- 88% complete to 3 A, 76% complete between 3 A and 2.4 A, spermidine conjugate, trypanothione [T(S)2] (Fig. 1) (2). and only 35% complete between 2.4 and 2.0 A. Finally, only Oxidized T(S)2 is reduced by the action of trypanothione data from 10 A to 2.4 A were used in the structure solution reductase (TR), a flavoprotein disulfide reductase that is by molecular replacement, and data from 6 A to 2.4 A were closely related to GR (5). TR was first characterized from an used for the refinement of the structure. insect trypanosomatid, Crithidia fasciculata, and is very Structure determination by molecular replacement used similar to GR in size, catalytic mechanism, and amino acid the 1.5-A structure of GR (13) as a search model with no sequence (5, 6). Both enzymes are dimeric and act by changes in the sequence and with all protein and FAD atoms transferring electrons from NADPH to an enzyme disulfide included. Calculations were carried out using the programs by way of FAD, followed by disulfide interchange with the X-PLOR (19) and MERLOT (20). A three-dimensional rotation substrate (5). However, human GR and TR are mutually function was calculated using a dimer of GR and x-ray data exclusive with regard to substrate (7). This, combined with for TR to 4.5-A resolution (19). The highest two peaks in the the known susceptibility of trypanosomatids to oxidative stress when GSSG synthesis is blocked (8, 9), makes TR a Abbreviations: GR, glutathione reductase; TR, trypanothione reduc- tase; GSSG, glutathione; T(S)2, trypanothine. IDeceased, September 24, 1990. The publication costs of this article were defrayed in part by page charge IThe atomic coordinates and structure factors have been deposited in payment. This article must therefore be hereby marked "advertisement" the Protein Data Bank, Chemistry Department, Brookhaven Na- in accordance with 18 U.S.C. §1734 solely to indicate this fact. tional Laboratory, Upton, NY 11973 (reference 2TPR, R2TPRSF). 8764 Downloaded by guest on September 26, 2021 Biochemistry: Kuriyan et al. Proc. Natl. Acad. Sci. USA 88 (1991) 8765 (+1) Spermidine -1 I y-Glu FIG. 1. Stereodiagram of T(S)2. The molecule is shown in the same orientation as in Figs. 3 and 4. The two tripeptides of Cys I GSSG are labeled I and II (4). The sper- midine crosslink between the glycine resi- dues is shown in thicker lines. Hydrogens +1 bonded to nitrogens are shown as open circles. Formal charges are indicated by the positive and negative numbers, with y-Glu H the charges that differ between GSSG and T(S)2 in parentheses [+1 in T(S)2 and -1 in -1 GSSG]. rotation function were at 4 standard deviations (e) above the been built as alanine residues. In addition, the last 6 residues mean and were related by a twofold rotation axis. The of the C terminus are not well-ordered and have not been orientation was further refined by Patterson-correlation re- included. finement (19), treating the entire dimer as a rigid body and with final correlation coefficients of 0.08 and 0.09 for these two peaks and 0.06 for the next highest. A two-dimensional RESULTS AND DISCUSSION translation function (19) revealed a single sharp peak with a The C. fasciculata TR sequence is very similar to that of height of8oabove the mean. With reference to the GR model, Trypanosoma congolense TR, with an overall sequence the orientation of the TR molecule in form III crystals identity of 68% (6, 25). The similarity to human GR is much corresponds to eulerian rotations of 61 = 1640, 92 = 680, 83 = lower, with 34% identity. Both TR sequences lack the 17 1000, with translations along a and c of 0.306 and 0.016 in N-terminal residues that are disordered in the GR x-ray fractional coordinates, respectively. structure and possess a C-terminal extension (19 residues in A combination of model building using FRODO (21) and C. fasciculata). There are two insertions relative to GR that conventional least-squares refinement using X-PLOR (22) al- are longer than three residues in both TR sequences: TR lowed most of the changes in the TR sequence (5) to be built, residues 38-46, between GR residues 53 and 54, and TR and the conventional crystallographic residual error (R) value residues 129-139, between residues 133 and 134 in GR (6). dropped from 52.5% to 28.9%o0 at 2.4-A resolution. At this The structure of TR closely resembles that of GR, as stage, x-ray-restrained molecular dynamics refinement (23) expected. The enzyme is dimeric, with two symmetrical was carried out using a previously described protocol (24). A active sites. Each monomer consists of four domains: the strong indication of the correctness of the model was the N-terminal FAD binding domain, the NADPH binding do- presence of readily interpretable electron density for inser- main, the central domain that also provides part of the FAD tions in the TR sequence (Fig. 2). The current model includes binding site, and the C-terminal interface domain. Each 3681 nonhydrogen protein and FAD atoms per subunit and substrate binding site is a deep crevice, at the base of which 128 water molecules.
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