6PQ3

Crystal structure of GDP-bound KRAS with ten residues long internal tandem duplication in the switch II region

6PQ3 の概要

• エントリーDOI: 10.2210/pdb6pq3/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: kras, ras, mg, k-ras, oncoprotein, gdp, internal tandem duplication, itd
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21409.84

構造登録者

Dharmaiah, S.,Chan, A.H.,Tran, T.H.,Simanshu, D.K. (登録日: 2019-07-08, 公開日: 2020-05-20, 最終更新日: 2023-10-11)

主引用文献

Nelson, A.C.,Turbyville, T.J.,Dharmaiah, S.,Rigby, M.,Yang, R.,Wang, T.Y.,Columbus, J.,Stephens, R.,Taylor, T.,Sciacca, D.,Onsongo, G.,Sarver, A.,Subramanian, S.,Nissley, D.V.,Simanshu, D.K.,Lou, E.
RASinternal tandem duplication disrupts GTPase-activating protein (GAP) binding to activate oncogenic signaling.
J.Biol.Chem., 295:9335-9348, 2020

PubMed Abstract: The oncogene RAS is one of the most widely studied proteins in cancer biology, and mutant active RAS is a driver in many types of solid tumors and hematological malignancies. Yet the biological effects of different mutations and the tissue-specific clinical implications are complex and nuanced. Here, we identified an internal tandem duplication (ITD) in the switch II domain of NRAS from a patient with extremely aggressive colorectal carcinoma. Results of whole-exome DNA sequencing of primary and metastatic tumors indicated that this mutation was present in all analyzed metastases and excluded the presence of any other clear oncogenic driver mutations. Biochemical analysis revealed increased interaction of the RAS ITD with Raf proto-oncogene Ser/Thr kinase (RAF), leading to increased phosphorylation of downstream MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK). The ITD prevented interaction with neurofibromin 1 (NF1)-GTPase-activating protein (GAP), providing a mechanism for sustained activity of the RAS ITD protein. We present the first crystal structures of NRAS and KRAS ITD at 1.65-1.75 Å resolution, respectively, providing insight into the physical interactions of this class of RAS variants with its regulatory and effector proteins. Our in-depth bedside-to-bench analysis uncovers the molecular mechanism underlying a case of highly aggressive colorectal cancer and illustrates the importance of robust biochemical and biophysical approaches in the implementation of individualized medicine.

PubMed: 32393580
DOI: 10.1074/jbc.RA119.011080

実験手法

X-RAY DIFFRACTION (1.75 Å)