Crystal Structures of Metallo-β-Lactamase (IMP-1) and Its D120E Mutant in Complexes with Citrate and the Inhibitory Effect of the Benzyl Group in Citrate Monobenzyl Ester
Crystal Structures of Metallo-β-Lactamase (IMP-1) and Its D120E Mutant in Complexes with Citrate and the Inhibitory Effect of the Benzyl Group in Citrate Monobenzyl Ester
复制标题
金属-β-内酰胺酶(IMP-1)及其D120E突变体与柠檬酸盐复合物的晶体结构及柠檬酸单苄酯中苄基的抑制作用
DOI：
10.1021/acs.jmedchem.1c00308
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kurosaki Hiromasa
中科院分区：
文献类型：
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作者：
Yamaguchi Yoshihiro;Kato Koichi;Ichimaru Yoshimi;Jin Wanchun;Sakai Misa;Abe Miki;Wachino Jun-ichi;Arakawa Yoshichika;Miyagi Yukina;Imai Masanori;Fukuishi Nobuyuki;Yamagata Yuriko;Otsuka Masami;Fujita Mikako;Kurosaki Hiromasa
产生金属β-内酰胺酶如IMP-1和NDM-1的碳青霉烯耐药病原体的出现和迅速传播已成为全球临床环境中非常关注的问题。粘质沙雷氏菌IMP-1及其单突变体D120E与柠檬酸盐配合物的x射线晶体结构分别以2.00和1.85 Å的分辨率测定。两个晶体结构表明，在位置120的单个突变引起Zn1周围的结构变化，其中几何形状从天然IMP-1的四面体变为D120E的方形金字塔。在此基础上，作者合成了柠檬酸单苯酯，考察其对IMP-1抑制活性的结构要求，并与未取代的柠檬酸酯进行了比较。与柠檬酸盐相比，在柠檬酸盐中引入苄基增强了抑制活性（IC50 bb0 5 mM）。
The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-β-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 fromSerratia marcescensand its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester1to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC50> 5 mM).