Berry College Department of Chemistry and Biochemistry, Mount Berry, Georgia 30149, United States.
Biochemistry. 2023 Aug 15;62(16):2503-2515. doi: 10.1021/acs.biochem.3c00165. Epub 2023 Jul 12.
Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The recent development of a class of drugs called "correctors", which repair the structure and function of mutant CFTR, has greatly enhanced the life expectancy of CF patients. These correctors target the most common disease causing CFTR mutant F508del and are exemplified by the FDA-approved VX-809. While one binding site of VX-809 to CFTR was recently elucidated by cryo-electron microscopy, four additional binding sites have been proposed in the literature and it has been theorized that VX-809 and structurally similar correctors may engage multiple CFTR binding sites. To explore these five binding sites, ensemble docking was performed on wild-type CFTR and the F508del mutant using a large library of structurally similar corrector drugs, including VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), and a host of other structurally related molecules. For wild-type CFTR, we find that only one site, located in membrane spanning domain 1 (MSD1), binds favorably to our ligand library. While this MSD1 site also binds our ligand library for F508del-CFTR, the F508del mutation also opens a binding site in nucleotide binding domain 1 (NBD1), which enables strong binding of our ligand library to this site. This NBD1 site in F508del-CFTR exhibits the strongest overall binding affinity for our library of corrector drugs. This data may serve to better understand the structural changes induced by mutation of CFTR and how correctors bind to the protein. Additionally, it may aid in the design of new, more effective CFTR corrector drugs.
囊性纤维化（CF）是一种隐性遗传疾病，由囊性纤维化跨膜电导调节因子（CFTR）蛋白的突变引起。最近开发的一类称为“校正剂”的药物，可修复突变 CFTR 的结构和功能，极大地提高了 CF 患者的预期寿命。这些校正剂针对最常见的致病 CFTR 突变 F508del，以 FDA 批准的 VX-809 为代表。虽然最近通过冷冻电子显微镜阐明了 VX-809 与 CFTR 的一个结合位点，但文献中提出了另外四个结合位点，并提出了 VX-809 和结构相似的校正剂可能与多个 CFTR 结合位点结合的理论。为了探索这五个结合位点，使用包括 VX-809（lumacaftor）、VX-661（tezacaftor）、ABBV-2222（galicaftor）和许多其他结构相关分子的结构相似校正药物的大型文库，对野生型 CFTR 和 F508del 突变体进行了整体对接。对于野生型 CFTR，我们发现只有一个位于跨膜域 1（MSD1）的位点有利于我们的配体文库结合。虽然这个 MSD1 位点也与我们的 F508del-CFTR 配体文库结合，但 F508del 突变还会打开核苷酸结合域 1（NBD1）中的一个结合位点，使我们的配体文库能够强烈结合到该位点。F508del-CFTR 中的这个 NBD1 位点对我们的校正药物文库具有最强的整体结合亲和力。该数据可用于更好地了解 CFTR 突变引起的结构变化以及校正剂如何与蛋白质结合。此外，它可能有助于设计新的、更有效的 CFTR 校正药物。
