Rice Univesrity Logo
    • FAQ
    • Deposit your work
    • Login
    View Item 
    •   Rice Scholarship Home
    • Faculty & Staff Research
    • Faculty Publications
    • View Item
    •   Rice Scholarship Home
    • Faculty & Staff Research
    • Faculty Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Structure-guided selection of specificity determining positions in the human Kinome

    Thumbnail
    Name:
    12864_2016_Article_2790.pdf
    Size:
    2.014Mb
    Format:
    PDF
    View/Open
    Author
    Moll, Mark; Finn, Paul W; Kavraki, Lydia E
    Date
    2016
    Abstract
    Abstract Background The human kinome contains many important drug targets. It is well-known that inhibitors of protein kinases bind with very different selectivity profiles. This is also the case for inhibitors of many other protein families. The increased availability of protein 3D structures has provided much information on the structural variation within a given protein family. However, the relationship between structural variations and binding specificity is complex and incompletely understood. We have developed a structural bioinformatics approach which provides an analysis of key determinants of binding selectivity as a tool to enhance the rational design of drugs with a specific selectivity profile. Results We propose a greedy algorithm that computes a subset of residue positions in a multiple sequence alignment such that structural and chemical variation in those positions helps explain known binding affinities. By providing this information, the main purpose of the algorithm is to provide experimentalists with possible insights into how the selectivity profile of certain inhibitors is achieved, which is useful for lead optimization. In addition, the algorithm can also be used to predict binding affinities for structures whose affinity for a given inhibitor is unknown. The algorithm’s performance is demonstrated using an extensive dataset for the human kinome. Conclusion We show that the binding affinity of 38 different kinase inhibitors can be explained with consistently high precision and accuracy using the variation of at most six residue positions in the kinome binding site. We show for several inhibitors that we are able to identify residues that are known to be functionally important.
    Citation
    Moll, Mark, Finn, Paul W and Kavraki, Lydia E. "Structure-guided selection of specificity determining positions in the human Kinome." BMC Genomics, 17(Suppl 4), (2016) BioMed Central: http://dx.doi.org/10.1186/s12864-016-2790-3.
    Published Version
    http://dx.doi.org/10.1186/s12864-016-2790-3
    Type
    Journal article
    Publisher
    BioMed Central
    Citable link to this page
    https://hdl.handle.net/1911/91258
    Rights
    This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
    Link to License
    https://creativecommons.org/licenses/by/4.0/
    Metadata
    Show full item record
    Collections
    • Computer Science Publications [142]
    • Faculty Publications [5245]

    Home | FAQ | Contact Us | Privacy Notice | Accessibility Statement
    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map

     

    Searching scope

    Browse

    Entire ArchiveCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsTypeThis CollectionBy Issue DateAuthorsTitlesSubjectsType

    My Account

    Login

    Statistics

    View Usage Statistics

    Home | FAQ | Contact Us | Privacy Notice | Accessibility Statement
    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map