Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study

© 2015 Informa UK Limited, trading as Taylor & Francis Group. Protein kinase C (PKC) isozymes are important regulatory enzymes that have been implicated in many diseases, including cancer, Alzheimer’s disease, and in the eradication of HIV/AIDS. Given their potential clinical ramifications, PK...

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Main Authors: Patcharapong Thangsunan, Suriya Tateing, Supa Hannongbua, Nuttee Suree
Format: Journal
Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/55176
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spelling th-cmuir.6653943832-551762018-09-05T02:52:46Z Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study Patcharapong Thangsunan Suriya Tateing Supa Hannongbua Nuttee Suree Biochemistry, Genetics and Molecular Biology © 2015 Informa UK Limited, trading as Taylor & Francis Group. Protein kinase C (PKC) isozymes are important regulatory enzymes that have been implicated in many diseases, including cancer, Alzheimer’s disease, and in the eradication of HIV/AIDS. Given their potential clinical ramifications, PKC modulators, e.g. phorbol esters and bryostatin, are also of great interest in the drug development. However, structural details on the binding between PKC and its modulators, especially bryostatin – the highly potent and non-tumor promoting activator for PKCs, are still lacking. Here, we report the first comparative molecular dynamics study aimed at gaining structural insight into the mechanisms by which the PKC delta cys2 activator domain is used in its binding to phorbol ester and bryostatin-1. As anticipated in the phorbol ester binding, hydrogen bonds are formed through the backbone atoms of Thr242, Leu251, and Gly253 of PKC. However, the opposition of H-bond formation between Thr242 and Gly253 may cause the phorbol ester complex to become less stable when compared with the bryostatin binding. For the PKC delta-bryostatin complex, hydrogen bonds are formed between the Gly253 backbone carbonyl and the C30 carbomethoxy substituent of the ligand. Additionally, the indole Nε1 of the highly homologous Trp252 also forms an H-bond to the C20 ester group on bryostatin. Backbone fluctuations also suggest that this latter H-bond formation may abrogate the transient interaction between Trp252 and His269, thus dampening the fluctuations observed on the nearby Zn2+-coordinating residues. This new dynamic fluctuation dampening model can potentially benefit future design of new PKC modulators. 2018-09-05T02:52:46Z 2018-09-05T02:52:46Z 2016-07-02 Journal 15380254 07391102 2-s2.0-84976533547 10.1080/07391102.2015.1084479 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84976533547&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/55176
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
spellingShingle Biochemistry, Genetics and Molecular Biology
Patcharapong Thangsunan
Suriya Tateing
Supa Hannongbua
Nuttee Suree
Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study
description © 2015 Informa UK Limited, trading as Taylor & Francis Group. Protein kinase C (PKC) isozymes are important regulatory enzymes that have been implicated in many diseases, including cancer, Alzheimer’s disease, and in the eradication of HIV/AIDS. Given their potential clinical ramifications, PKC modulators, e.g. phorbol esters and bryostatin, are also of great interest in the drug development. However, structural details on the binding between PKC and its modulators, especially bryostatin – the highly potent and non-tumor promoting activator for PKCs, are still lacking. Here, we report the first comparative molecular dynamics study aimed at gaining structural insight into the mechanisms by which the PKC delta cys2 activator domain is used in its binding to phorbol ester and bryostatin-1. As anticipated in the phorbol ester binding, hydrogen bonds are formed through the backbone atoms of Thr242, Leu251, and Gly253 of PKC. However, the opposition of H-bond formation between Thr242 and Gly253 may cause the phorbol ester complex to become less stable when compared with the bryostatin binding. For the PKC delta-bryostatin complex, hydrogen bonds are formed between the Gly253 backbone carbonyl and the C30 carbomethoxy substituent of the ligand. Additionally, the indole Nε1 of the highly homologous Trp252 also forms an H-bond to the C20 ester group on bryostatin. Backbone fluctuations also suggest that this latter H-bond formation may abrogate the transient interaction between Trp252 and His269, thus dampening the fluctuations observed on the nearby Zn2+-coordinating residues. This new dynamic fluctuation dampening model can potentially benefit future design of new PKC modulators.
format Journal
author Patcharapong Thangsunan
Suriya Tateing
Supa Hannongbua
Nuttee Suree
author_facet Patcharapong Thangsunan
Suriya Tateing
Supa Hannongbua
Nuttee Suree
author_sort Patcharapong Thangsunan
title Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study
title_short Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study
title_full Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study
title_fullStr Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study
title_full_unstemmed Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study
title_sort structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase c: a comparative molecular dynamics simulation study
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84976533547&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/55176
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