5O2S

Human KRAS in complex with darpin K27

5O2S の概要

• エントリーDOI: 10.2210/pdb5o2s/pdb
• 分子名称: GTPase KRas, darpin K27, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: kras, ras signalling, darpin, nucleotide exchange, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 156828.29

構造登録者

Debreczeni, J.E.,Guillard, S.,Kolasinska-Zwierz, P.,Breed, J.,Zhang, J.,Bery, N.,Marwood, R.,Tart, J.,Stocki, P.,Mistry, B.,Phillips, C.,Rabbitts, T.,Jackson, R.,Minter, R. (登録日: 2017-05-22, 公開日: 2017-07-26, 最終更新日: 2024-05-08)

主引用文献

Guillard, S.,Kolasinska-Zwierz, P.,Debreczeni, J.,Breed, J.,Zhang, J.,Bery, N.,Marwood, R.,Tart, J.,Overman, R.,Stocki, P.,Mistry, B.,Phillips, C.,Rabbitts, T.,Jackson, R.,Minter, R.
Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange.
Nat Commun, 8:16111-16111, 2017

PubMed Abstract: Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a K of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.

PubMed: 28706291
DOI: 10.1038/ncomms16111

実験手法

X-RAY DIFFRACTION (3.22 Å)