Pathological role of a point mutation (T315I) in BCR-ABL1 proteinA computational insight

被引:104
作者
Rajendran, Vidya [1 ]
Gopalakrishnan, Chandrasekhar [2 ]
Sethumadhavan, Rao [1 ]
机构
[1] Vellore Inst Technol Univ, Computat Biol Lab, Dept Biotechnol, Vellore 632014, Tamil Nadu, India
[2] Univ Calgary, Dept Biochem & Mol Biol, Cumming Sch Med, Calgary, AB, Canada
关键词
BCR-ABL protein; dynamics simulation; flexibility; mutation; CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; KINASE DOMAIN MUTATIONS; ABL TYROSINE KINASE; BCR-ABL; PHILADELPHIA-CHROMOSOME; MOLECULAR-DYNAMICS; C-ABL; INHIBITOR; NILOTINIB;
D O I
10.1002/jcb.26257
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
BCR-ABL protein is one of the most potent target to treat chronic myeloid leukemia (CML). Apart from other mutations, T315I is especially challenging as it confers resistance to all first- and second-generation tyrosine kinase inhibitors. So, a thorough study of altered behavior upon mutation is crucially needed. To understand the resistance mechanism of mutant BCR-ABL protein, we organized a long-term molecular dynamics simulation (500ns) and performed the detailed comparative conformational analysis. We found that due to mutation at 315th position (threonine to isoleucine), original structures deviated from normal, and attained a flexible conformation. Our observations pave a clear path toward designing new inhibitors against resistant BCR-ABL1 protein and suggest a strategy where additional flexibility governed by mutation could be given an appropriate consideration.
引用
收藏
页码:918 / 925
页数:8
相关论文
共 50 条
[21]   Overcoming Bcr-Abl T315I mutation by combination of GNF-2 and ATP competitors in an Abl-independent mechanism [J].
Khateb, Mamduh ;
Ruimi, Nili ;
Khamisie, Hazem ;
Najajreh, Yousef ;
Mian, Afsar ;
Metodieva, Anna ;
Ruthardt, Martin ;
Mahajna, Jamal .
BMC CANCER, 2012, 12
[22]   Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment [J].
Oaxaca, Derrick M. ;
Yang-Reid, Sun Ah ;
Ross, Jeremy A. ;
Rodriguez, Georgialina ;
Staniswalis, Joan G. ;
Kirken, Robert A. .
TUMOR BIOLOGY, 2016, 37 (09) :12643-12654
[23]   The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins [J].
You, Liangshun ;
Liu, Hui ;
Huang, Jian ;
Xie, Wanzhuo ;
Wei, Jueying ;
Ye, Xiujin ;
Qian, Wenbin .
ONCOTARGET, 2017, 8 (05) :7777-7790
[24]   Computer Modeling and Synthesis of Potential Inhibitors of Tyrosine Kinase BCR-ABL with the T315I Mutation [J].
Fedarkevich, A. N. ;
Sharko, O. L. ;
Shmanai, V. V. .
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, 2020, 46 (02) :187-198
[25]   The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL [J].
Mian, A. A. ;
Schuell, M. ;
Zhao, Z. ;
Oancea, C. ;
Hundertmark, A. ;
Beissert, T. ;
Ottmann, O. G. ;
Ruthardt, M. .
LEUKEMIA, 2009, 23 (09) :1614-1621
[26]   Inhibitory effect of the anthelmintic drug pyrvinium pamoate on T315I BCR-ABL-positive CML cells [J].
Zhang, Jing ;
Jin, Yanli ;
Pan, Jingxuan .
MOLECULAR MEDICINE REPORTS, 2017, 16 (06) :9217-9223
[27]   Allogeneic Stem Cell Transplantation for Patients with T315I BCR-ABL Mutated Chronic Myeloid Leukemia [J].
Xu, Lan-Ping ;
Xu, Zheng-Li ;
Zhang, Xiao-Hui ;
Chen, Huan ;
Chen, Yu-Hong ;
Han, Wei ;
Chen, Yao ;
Wang, Feng-Rong ;
Wang, Jing-Zhi ;
Wang, Yu ;
Yan, Chen-Hua ;
Mo, Xiao-Dong ;
Liu, Kai-Yan ;
Huang, Xiao-Jun .
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2016, 22 (06) :1080-1086
[28]   Introduction of the T315I gatekeeper mutation of BCR/ABL1 into a Philadelphia chromosome-positive lymphoid leukemia cell line using the CRISPR/Cas9 system [J].
Nguyen, Thao T. T. ;
Tamai, Minori ;
Harama, Daisuke ;
Kagami, Keiko ;
Kasai, Shin ;
Watanabe, Atsushi ;
Akahane, Koshi ;
Goi, Kumiko ;
Inukai, Takeshi .
INTERNATIONAL JOURNAL OF HEMATOLOGY, 2022, 116 (04) :534-543
[29]   Structure optimization, synthesis and bioactivity evaluation of novel BCR-ABL tyrosine kinase inhibitor targeting T315I mutation [J].
Wang, Shuo ;
Chen, Jingjing ;
Hou, Rui ;
Xiong, Yijing ;
Shi, Huaihuai ;
Chen, Zhesheng ;
Li, Jiazhong ;
Wang, Xin .
CHEMICO-BIOLOGICAL INTERACTIONS, 2024, 403
[30]   Serial monitoring of T315I BCR-ABL mutation by Invader assay combined with RT-PCR [J].
Masahide Yamamoto ;
Kazuhiko Kakihana ;
Kazuteru Ohashi ;
Toshikazu Yamaguchi ;
Kenichi Tadokoro ;
Hideki Akiyama ;
Hisashi Sakamaki .
International Journal of Hematology, 2009, 89 :482-488