1f3b
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CRYSTAL STRUCTURE OF MGSTA1-1 IN COMPLEX WITH GLUTATHIONE CONJUGATE OF BENZO[A]PYRENE EPOXIDE
OverviewOverview
Murine class alpha glutathione S-transferase A1-1 (mGSTA1-1), unlike, mammalian class alpha GSTs, is the most efficient in the glutathione (GSH), conjugation of the ultimate carcinogenic metabolite of benzo[a]pyrene, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9, 10-tetrahydrobenzo[a]pyrene, [(+)-anti-BPDE] [Hu, X., Srivastava, S. K., Xia, H., Awasthi, Y. C., and, Singh, S. V. (1996) J. Biol. Chem. 271, 32684-32688]. Here, we report the, crystal structures of mGSTA1-1 in complex with GSH and with the GSH, conjugate of (+)-anti-BPDE (GSBpd) at 1.9 and 2.0 A resolution, respectively. Both crystals belong to monoclinic space group C2 with one, dimer in the asymmetric unit. The structures reveal that, within one, subunit, the GSH moiety interacts with residues Y8, R14, K44, Q53, V54, Q66, and T67, whereas the hydrophobic moiety of GSBpd interacts with the, side chains of F9, R14, M207, A215, R216, F219, and I221. In addition, the, GSH moiety interacts with D100 and R130 from the other subunit across the, dimer interface. The structural comparison between mGSTA1-1.GSH and, mGSTA1-1.GSBpd reveals significant conformational differences. The, movement of helix alpha9 brings the residues on the helix into direct, interaction with the product. Most noticeable are the positional, displacement and conformational change of R216, one of the residues, located in helix alpha9. The side chain of R216, which points away from, the H-site in the mGSTA1-1.GSH complex, probes into the active site and, becomes parallel with the aromatic ring system of GSBpd. Moreover, the, guanidinium group of R216 shifts approximately 8 A and forms a strong, hydrogen bond with the C8 hydroxyl group of GSBpd, suggesting that the, electrostatic assistance provided by the guanidinium group facilitates the, ring-opening reaction of (+)-anti-BPDE. The structure of mGSTA1-1. GSBpd, is also compared with those of hGSTP1-1[V104,A113].GSBpd, hGSPA1-1.S-benzylglutathione, and mGSTA4-4., 4-S-glutathionyl-5-pentyltetrahydrofuran-2-ol. The comparison provides, further evidence that supports the functional roles of R216 and helix, alpha9. The lack of mobility of helix alpha9 and/or the lack of, electrostatic assistance from R216 may be responsible for the relatively, lower activity of hGSTA1-1, mGSTA4-4, and hGSTP1-1 toward (+)-anti-BPDE.
About this StructureAbout this Structure
1F3B is a Single protein structure of sequence from Mus musculus with GBX as ligand. Active as Glutathione transferase, with EC number 2.5.1.18 Full crystallographic information is available from OCA.
ReferenceReference
Residue R216 and catalytic efficiency of a murine class alpha glutathione S-transferase toward benzo[a]pyrene 7(R),8(S)-diol 9(S), 10(R)-epoxide., Gu Y, Singh SV, Ji X, Biochemistry. 2000 Oct 17;39(41):12552-7. PMID:11027134
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