最近有报道称KRASG12C抑制剂对肺癌患者有效，它与非活性或二磷酸鸟苷（GDP）结合的癌蛋白状态结合，需要三磷酸鸟苷（GTP）的水解来进行抑制。然而，KRAS突变阻止了GTP酶激活蛋白（GAP）的催化精氨酸提高原本缓慢的水解率。如果KRAS突变体确实对GAP不敏感，目前还不清楚KRASG12C如何水解足够的GTP来实现非活性状态的选择性抑制。
研究人员发现RGS3，一种以前已知的调节G蛋白偶联受体的GAP，也能增强突变体和野生型KRAS蛋白的GTP酶活性。这项研究揭示了一种意想不到的使KRAS失活的机制，并解释了新兴临床疗法的弱点。
附：英文原文
Title: The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS
Author: Chuanchuan Li, Alberto Vides, Dongsung Kim, Jenny Y. Xue, Yulei Zhao, Piro Lito
Issue&Volume: 2021-10-08
Abstract: Recently reported to be effective in patients with lung cancer, KRASG12C inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRASG12C hydrolyzes sufficient GTP to allow inactive state–selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein–coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.
DOI: abf1730
Source: https://www.science.org/doi/10.1126/science.abf1730