5UUT

N-myristoyltransferase 1 (NMT) bound to myristoyl-CoA

5UUT の概要

• エントリーDOI: 10.2210/pdb5uut/pdb
• 分子名称: Glycylpeptide N-tetradecanoyltransferase 1, TETRADECANOYL-COA, CITRIC ACID, ... (4 entities in total)
• 機能のキーワード: myristoylation, myristoyl-coa, cancer, co/post-translational modification, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93246.72

構造登録者

Goodwin, O.,Pegan, S. (登録日: 2017-02-17, 公開日: 2018-01-17, 最終更新日: 2024-03-06)

主引用文献

Kim, S.,Alsaidan, O.A.,Goodwin, O.,Li, Q.,Sulejmani, E.,Han, Z.,Bai, A.,Albers, T.,Beharry, Z.,Zheng, Y.G.,Norris, J.S.,Szulc, Z.M.,Bielawska, A.,Lebedyeva, I.,Pegan, S.D.,Cai, H.
Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression.
Cancer Res., 77:6950-6962, 2017

PubMed Abstract: Protein -myristoylation enables localization to membranes and helps maintain protein conformation and function. -myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the -myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. .

PubMed: 29038344
DOI: 10.1158/0008-5472.CAN-17-0981

実験手法

X-RAY DIFFRACTION (2.252 Å)