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首页> 外文期刊>Biochemistry >CRYSTAL STRUCTURE OF GLYCOSOMAL GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE FROM LEISHMANIA MEXICANA - IMPLICATIONS FOR STRUCTURE-BASED DRUG DESIGN AND A NEW POSITION FOR THE INORGANIC PHOSPHATE BINDING SITE
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CRYSTAL STRUCTURE OF GLYCOSOMAL GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE FROM LEISHMANIA MEXICANA - IMPLICATIONS FOR STRUCTURE-BASED DRUG DESIGN AND A NEW POSITION FOR THE INORGANIC PHOSPHATE BINDING SITE

机译：墨西哥利什曼原虫的糖醛酸甘油醛3-磷酸脱氢酶的晶体结构-对基于药物的药物设计的意义以及无机磷酸盐结合位点的新地位

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摘要

The structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the trypanosomatid parasite Leishmania mexicana has been determined by X-ray crystallography. The protein crystallizes in space group P2(1)2(1)2(1) With unit cell parameters a = 99.0 Angstrom, b = 126.5 Angstrom, and c = 138.9 Angstrom. There is one 156 000 Da protein tetramer per asymmetric unit. The model of the protein with bound NAD(+)s and phosphates has been refined against 86% complete data from 10.0 to 2.8 Angstrom to a crystallographic R(factor) of 0.198. Density modification by noncrystallographic symmetry averaging was used during model building. The final model of the L. mexicana GAPDH tetramer shows small deviations of less than 0.5 degrees from ideal 222 molecular symmetry. The structure of L. mexicana GAPDK is very similar to that of glycosomal GAPDH from the related trypanosomatid Trypanosoma brucei. A significant structural difference between L. mexicana GAPDH and most previously determined GAPDH structures occurs in a loop region located at the active site. This unusual loop conformation in L. mexicana GAPDH occludes the inorganic phosphate binding site which has been seen in previous GAPDH structures. A new inorganic phosphate position is observed in the L. mexicana GAPDH structure. Model building studies indicate that this new anion binding site is well situated for nucleophilic attack of the inorganic phosphate on the thioester intermediate in the GAPDH-catalyzed reaction. Since crystals of L. mexicana GAPDH can be grown reproducibly and diffract much better than those of T. brucei GAPDH, L. mexicana GAPDH will be used as a basis for structure-based drug design targeted against trypanosomatid GAPDHs.
机译：通过X射线晶体学确定了锥虫的寄生虫Leishmania mexicana的糖体甘油醛-3-磷酸脱氢酶（GAPDH）的结构。该蛋白质在空间单元P2（1）2（1）2（1）中结晶，其晶胞参数a = 99.0埃，b = 126.5埃，c = 138.9埃。每个不对称单位有一个156 000 Da蛋白四聚体。结合了NAD（+）s和磷酸盐的蛋白质模型已针对10.0至2.8埃的86％完整数据进行了精修，结晶度R（因子）为0.198。在模型构建过程中，使用了非晶体对称平均法进行的密度修正。墨西哥乳杆菌GAPDH四聚体的最终模型显示出与理想222分子对称性的小于0.5度的小偏差。墨西哥乳杆菌GAPDK的结构与相关锥虫锥虫锥虫糖体GAPDH的结构非常相似。墨西哥乳杆菌GAPDH和最先确定的GAPDH结构之间的显着结构差异发生在位于活性位点的环区域中。墨西哥乳杆菌GAPDH中这种不寻常的环构象阻塞了先前的GAPDH结构中所见的无机磷酸盐结合位点。在墨西哥乳杆菌GAPDH结构中观察到新的无机磷酸盐位置。模型构建研究表明，该新的阴离子结合位点正好位于GAPDH催化的反应中，无机磷酸盐对硫酯中间体的亲核攻击。由于墨西哥乳杆菌GAPDH的晶体可再现地生长并且衍射比布鲁氏杆菌GAPDH更好，因此，墨西哥乳杆菌GAPDH将被用作针对锥虫的GAPDH的基于结构的药物设计的基础。

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