Kim H, Certa U, Döbeli H, Jakob P, Hol W G
Howard Hughes Medical Institute and Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Biochemistry. 1998 Mar 31;37(13):4388-96. doi: 10.1021/bi972233h.
The structure of the glycolytic enzyme class I fructose-1, 6-bisphosphate aldolase from the human malaria parasite Plasmodium falciparum has been determined by X-ray crystallography. Homotetrameric P. falciparum aldolase (PfALDO) crystallizes in space group P3221 with one 80 kDa dimer per asymmetric unit. The final refined PfALDO model has an R-factor of 0.239 and an R-free of 0.329 with respect to data from 8 to 3.0 A resolution. PfALDO is potentially a target for antimalarial drug design as the intraerythrocytic merozoite lifestage of P. falciparum is completely dependent upon glycolysis for its ATP production. Thus, inhibitors directed against the glycolytic enzymes in P. falciparum may be effective in killing the parasite. The structure of PfALDO is compared with the previously determined structure of human aldolase in order to determine possible targets for the structure-based design of selective PfALDO ligands. The salient structural differences include a hydrophobic pocket on the surface of PfALDO, which results from some amino acid changes and a single residue deletion compared with human aldolase, and the overall quaternary structure of the PfALDO tetramer, which buries less surface area than human aldolase.
通过X射线晶体学确定了来自人类疟原虫恶性疟原虫的糖酵解酶I类果糖-1,6-二磷酸醛缩酶的结构。恶性疟原虫醛缩酶（PfALDO）为同四聚体，在空间群P3221中结晶，每个不对称单元有一个80 kDa的二聚体。最终精修的PfALDO模型相对于8至3.0 Å分辨率的数据，R因子为0.239，自由R因子为0.329。PfALDO可能是抗疟药物设计的靶点，因为恶性疟原虫红细胞内裂殖子生活阶段完全依赖糖酵解来产生ATP。因此，针对恶性疟原虫糖酵解酶的抑制剂可能有效杀死该寄生虫。将PfALDO的结构与先前确定的人醛缩酶结构进行比较，以确定基于结构设计选择性PfALDO配体的可能靶点。显著的结构差异包括PfALDO表面的一个疏水口袋，这是由一些氨基酸变化和与人醛缩酶相比的单个残基缺失导致的，以及PfALDO四聚体的整体四级结构，其掩埋的表面积比人醛缩酶少。
