5VXZ

High-affinity AXL decoy receptor

5VXZ の概要

• エントリーDOI: 10.2210/pdb5vxz/pdb
• 分子名称: Growth arrest-specific protein 6, Tyrosine-protein kinase receptor UFO, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: engineered decoy receptor, human cancers, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 111257.46

構造登録者

Mathrews, I.I.,Kapur, S.,Kariolis, M.S.,Cochran, J.R. (登録日: 2017-05-24, 公開日: 2017-06-21, 最終更新日: 2024-11-06)

主引用文献

Kariolis, M.S.,Miao, Y.R.,Diep, A.,Nash, S.E.,Olcina, M.M.,Jiang, D.,Jones, D.S.,Kapur, S.,Mathews, I.I.,Koong, A.C.,Rankin, E.B.,Cochran, J.R.,Giaccia, A.J.
Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies.
J. Clin. Invest., 127:183-198, 2017

PubMed Abstract: The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Moreover, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.

PubMed: 27893463
DOI: 10.1172/JCI85610

実験手法

X-RAY DIFFRACTION (2.3 Å)