Journal:Acta Cryst F:S2053230X19001213
From Proteopedia
Substrate analogue complex structure of Mycobacterium tuberculosis decaprenyl diphosphate synthaseTzu-Ping Ko, Xiansha Xiao, Rey-Ting Guo, Jian-Wen Huang, Weidong Liu, Chun-Chi Chen [1] Molecular Tour . The two monomers in an asymmetric unit of the MtDPPS crystal are shown as ribbon diagrams. The β-strands are named A-F and the α-helices numbered 1-7 from N to C terminus. They are colored yellow/red for one subunit and magenta/cyan for the other. The reaction catalyzed by Rv2361c (or M. tuberculosis DPP synthase, MtDPPS) is very similar to that of undecaprenyl diphosphate synthase (UPPS), except for the chain length of the final product (C50 vs C55) and the starting allylic substrate (EZ-FPP vs EE-FPP). In fact, most cis-PTs share a common dimeric architecture, and the conserved S1 and S2 sites for substrate binding are located near the subunit interface. The starting allylic substrate is bound to the S1 site and the homoallylic substrate to be incorporated is bound to the S2 site. An invariant aspartate residue plays a central role in the catalysis by coordinating the Mg2+-bound substrates. The head-to-tail coupling reaction of cis-PT proceeds through a concerted pathway similar to the ionization-condensation-elimination mechanism of trans-PT. After the new C-C bond formation, the pyrophosphate leaves the S1 site along with Mg2+, and the resulting prenyl diphosphate switches from the S2 site to the S1 site (see static image below).  . The MtDPPS dimer is superimposed on itself with the two polypeptide chains switched. The protein is colored cyan/green in one dimer and pink/yellow in the other, and so are the side chains and the ligands, which are shown as stick models. Mg and water molecules are shown as spheres, and the coordinate bonds as dashed lines. Location of the S1 and S2 site as well as the nearby helices α1/α2 and strand βB are also indicated. When the S1 and S2 substrates and Mg are properly bound for catalysis, the . The (the asterisks denote residues from the counter-subunit in a dimer). , which is no longer engaged in Mg-coordination. The , and in the other it is also close to the β-phosphate of the S2 substrate. After the formation of new cis-double bond, the S1 pyrophosphate dissociates as an Mg complex, and Arg292* binds to the β-phosphate of the product and transfers it to the S1 site (see static image below). While the five-carbon longer hydrocarbon tail needs structural rearrangements to fit into the S1 pocket, the diphosphate moiety may be disposed like those of the GSPP conformers before it assumes a productive binding mode for the next cycle of reaction.  PDB reference: Rv2361c, 6ime. References
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