一种与抗原结合的抗肿瘤抗体的X射线结构。

The x-ray structure of an anti-tumour antibody in complex with antigen.

作者信息

Jeffrey P D, Bajorath J, Chang C Y, Yelton D, Hellström I, Hellström K E, Sheriff S

机构信息

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

出版信息

Nat Struct Biol. 1995 Jun;2(6):466-71. doi: 10.1038/nsb0695-466.

DOI:10.1038/nsb0695-466

PMID:7664109

Abstract

The crystal structures of the murine BR96 Fab and its human chimera have been determined in complex with the nonoate methyl ester derivative of Lewis Y (nLey) at 2.8 A and 2.5 A resolution, respectively. BR96 binds the carbohydrate in a large pocket which is formed by residues of all CDR loops except L2. The binding of the carbohydrate is mediated predominantly by aromatic residues in BR96. Analysis of the structure suggests that BR96 is capable of recognizing a structure larger than the Le(y) tetrasaccharide, providing a possible explanation for its high tumour selectivity. The structure provides a rationale for mutagenesis experiments that have resulted in BR96 CDR loop mutants with increased affinity for nLey and/or tumour cells.

摘要

已分别以2.8埃和2.5埃的分辨率测定了鼠源BR96 Fab及其人源嵌合体与Lewis Y（nLey）的壬酸甲酯衍生物形成复合物时的晶体结构。BR96在一个大口袋中结合碳水化合物，该口袋由除L2外所有CDR环的残基形成。碳水化合物的结合主要由BR96中的芳香族残基介导。结构分析表明，BR96能够识别比Le（y）四糖更大的结构，这为其高肿瘤选择性提供了一种可能的解释。该结构为诱变实验提供了理论依据，这些实验产生了对nLey和/或肿瘤细胞亲和力增加的BR96 CDR环突变体。