Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion

The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well‐characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107)...

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Autores principales: Sun, Zhongya, Zhang, Hao, Zhang, Yuanyuan, Liao, Liping, Zhou, Wen, Zhang, Fengcai, Lian, Fulin, Huang, Jing, Xu, Pan, Zhang, Rukang, Lu, Wenchao, Zhu, Mingrui, Tao, Hongru, Yang, Feng, Ding, Hong, Chen, Shijie, Yue, Liyan, Zhou, Bing, Zhang, Naixia, Tan, Minjia, Jiang, Hualiang, Chen, Kaixian, Liu, Bo, Liu, Chuanpeng, Dang, Yongjun, Luo, Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375240/
https://www.ncbi.nlm.nih.gov/pubmed/32714746
http://dx.doi.org/10.1002/advs.202000098
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author Sun, Zhongya
Zhang, Hao
Zhang, Yuanyuan
Liao, Liping
Zhou, Wen
Zhang, Fengcai
Lian, Fulin
Huang, Jing
Xu, Pan
Zhang, Rukang
Lu, Wenchao
Zhu, Mingrui
Tao, Hongru
Yang, Feng
Ding, Hong
Chen, Shijie
Yue, Liyan
Zhou, Bing
Zhang, Naixia
Tan, Minjia
Jiang, Hualiang
Chen, Kaixian
Liu, Bo
Liu, Chuanpeng
Dang, Yongjun
Luo, Cheng
author_facet Sun, Zhongya
Zhang, Hao
Zhang, Yuanyuan
Liao, Liping
Zhou, Wen
Zhang, Fengcai
Lian, Fulin
Huang, Jing
Xu, Pan
Zhang, Rukang
Lu, Wenchao
Zhu, Mingrui
Tao, Hongru
Yang, Feng
Ding, Hong
Chen, Shijie
Yue, Liyan
Zhou, Bing
Zhang, Naixia
Tan, Minjia
Jiang, Hualiang
Chen, Kaixian
Liu, Bo
Liu, Chuanpeng
Dang, Yongjun
Luo, Cheng
author_sort Sun, Zhongya
collection PubMed
description The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well‐characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well‐conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC‐Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC‐Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC‐Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti‐metastasis drug development, and also provides a novel strategy for inhibitor discovery toward “undruggable” protein targets.
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spelling pubmed-73752402020-07-23 Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion Sun, Zhongya Zhang, Hao Zhang, Yuanyuan Liao, Liping Zhou, Wen Zhang, Fengcai Lian, Fulin Huang, Jing Xu, Pan Zhang, Rukang Lu, Wenchao Zhu, Mingrui Tao, Hongru Yang, Feng Ding, Hong Chen, Shijie Yue, Liyan Zhou, Bing Zhang, Naixia Tan, Minjia Jiang, Hualiang Chen, Kaixian Liu, Bo Liu, Chuanpeng Dang, Yongjun Luo, Cheng Adv Sci (Weinh) Full Papers The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well‐characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well‐conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC‐Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC‐Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC‐Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti‐metastasis drug development, and also provides a novel strategy for inhibitor discovery toward “undruggable” protein targets. John Wiley and Sons Inc. 2020-05-13 /pmc/articles/PMC7375240/ /pubmed/32714746 http://dx.doi.org/10.1002/advs.202000098 Text en © 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full Papers
Sun, Zhongya
Zhang, Hao
Zhang, Yuanyuan
Liao, Liping
Zhou, Wen
Zhang, Fengcai
Lian, Fulin
Huang, Jing
Xu, Pan
Zhang, Rukang
Lu, Wenchao
Zhu, Mingrui
Tao, Hongru
Yang, Feng
Ding, Hong
Chen, Shijie
Yue, Liyan
Zhou, Bing
Zhang, Naixia
Tan, Minjia
Jiang, Hualiang
Chen, Kaixian
Liu, Bo
Liu, Chuanpeng
Dang, Yongjun
Luo, Cheng
Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
title Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
title_full Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
title_fullStr Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
title_full_unstemmed Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
title_short Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
title_sort covalent inhibitors allosterically block the activation of rho family proteins and suppress cancer cell invasion
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375240/
https://www.ncbi.nlm.nih.gov/pubmed/32714746
http://dx.doi.org/10.1002/advs.202000098
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