Karthikeyan S, Leung T, Ladias J A
Molecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2001 Jun 8;276(23):19683-6. doi: 10.1074/jbc.C100154200. Epub 2001 Apr 13.
The PDZ1 domain of the Na(+)/H(+) exchanger regulatory factor (NHERF) binds with nanomolar affinity to the carboxyl-terminal sequence QDTRL of the cystic fibrosis transmembrane conductance regulator (CFTR) and plays a central role in the cellular localization and physiological regulation of this chloride channel. The crystal structure of human NHERF PDZ1 bound to the carboxyl-terminal peptide QDTRL has been determined at 1.7-A resolution. The structure reveals the specificity and affinity determinants of the PDZ1-CFTR interaction and provides insights into carboxyl-terminal leucine recognition by class I PDZ domains. The peptide ligand inserts into the PDZ1 binding pocket forming an additional antiparallel beta-strand to the PDZ1 beta-sheet, and an extensive network of hydrogen bonds and hydrophobic interactions stabilize the complex. Remarkably, the guanido group of arginine at position -1 of the CFTR peptide forms two salt bridges and two hydrogen bonds with PDZ1 residues Glu(43) and Asn(22), respectively, providing the structural basis for the contribution of the penultimate amino acid of the peptide ligand to the affinity of the interaction.
钠氢交换调节因子（NHERF）的PDZ1结构域以纳摩尔亲和力与囊性纤维化跨膜传导调节因子（CFTR）的羧基末端序列QDTRL结合，并在该氯离子通道的细胞定位和生理调节中发挥核心作用。已确定与羧基末端肽QDTRL结合的人NHERF PDZ1的晶体结构，分辨率为1.7埃。该结构揭示了PDZ1-CFTR相互作用的特异性和亲和力决定因素，并为I类PDZ结构域对羧基末端亮氨酸的识别提供了见解。肽配体插入PDZ1结合口袋，形成与PDZ1β-折叠额外的反平行β-链，广泛的氢键和疏水相互作用网络稳定了复合物。值得注意的是，CFTR肽-1位精氨酸的胍基分别与PDZ1残基Glu(43)和Asn(22)形成两个盐桥和两个氢键，为肽配体倒数第二个氨基酸对相互作用亲和力的贡献提供了结构基础。
