Discovery of Rab1 binding sites using an ensemble of clustering methods

Suryani Lukman, Minh N. Nguyen, Kelvin Sim, Jeremy Teo

    Research output: Contribution to journalArticle

    Abstract

    Targeting non-native-ligand binding sites for potential investigative and therapeutic applications is an attractive strategy in proteins that share common native ligands, as in Rab1 protein. Rab1 is a subfamily member of Rab proteins, which are members of Ras GTPase superfamily. All Ras GTPase superfamily members bind to native ligands GTP and GDP, that switch on and off the proteins, respectively. Rab1 is physiologically essential for autophagy and transport between endoplasmic reticulum and Golgi apparatus. Pathologically, Rab1 is implicated in human cancers, a neurodegenerative disease, cardiomyopathy, and bacteria-caused infectious diseases. We have performed structural analyses on Rab1 protein using a unique ensemble of clustering methods, including multi-step principal component analysis, non-negative matrix factorization, and independent component analysis, to better identify representative Rab1 proteins than the application of a single clustering method alone does. We then used the identified representative Rab1 structures, resolved in multiple ligand states, to map their known and novel binding sites. We report here at least a novel binding site on Rab1, involving Rab1-specific residues that could be further explored for the rational design and development of investigative probes and/or therapeutic small molecules against the Rab1 protein. Proteins 2017; 85:859–871.

    Original languageEnglish (US)
    Pages (from-to)859-871
    Number of pages13
    JournalProteins: Structure, Function and Bioinformatics
    Volume85
    Issue number5
    DOIs
    StatePublished - May 1 2017

    Fingerprint

    rab1 GTP-Binding Proteins
    Cluster Analysis
    Binding Sites
    Ligands
    ras Proteins
    Proteins
    Neurodegenerative diseases
    Autophagy
    Independent component analysis
    Golgi Apparatus
    Guanosine Triphosphate
    Principal Component Analysis
    Factorization
    Cardiomyopathies
    Endoplasmic Reticulum
    Neurodegenerative Diseases
    Principal component analysis
    Communicable Diseases
    Bacteria
    Switches

    Keywords

    • allosteric site
    • binding site
    • drug design
    • GTPase
    • molecular recognition
    • protein flexibility
    • structural bioinformatics
    • structural clustering

    ASJC Scopus subject areas

    • Structural Biology
    • Biochemistry
    • Molecular Biology

    Cite this

    Discovery of Rab1 binding sites using an ensemble of clustering methods. / Lukman, Suryani; Nguyen, Minh N.; Sim, Kelvin; Teo, Jeremy.

    In: Proteins: Structure, Function and Bioinformatics, Vol. 85, No. 5, 01.05.2017, p. 859-871.

    Research output: Contribution to journalArticle

    Lukman, Suryani ; Nguyen, Minh N. ; Sim, Kelvin ; Teo, Jeremy. / Discovery of Rab1 binding sites using an ensemble of clustering methods. In: Proteins: Structure, Function and Bioinformatics. 2017 ; Vol. 85, No. 5. pp. 859-871.
    @article{7daec060ea92497790b467808a7f474d,
    title = "Discovery of Rab1 binding sites using an ensemble of clustering methods",
    abstract = "Targeting non-native-ligand binding sites for potential investigative and therapeutic applications is an attractive strategy in proteins that share common native ligands, as in Rab1 protein. Rab1 is a subfamily member of Rab proteins, which are members of Ras GTPase superfamily. All Ras GTPase superfamily members bind to native ligands GTP and GDP, that switch on and off the proteins, respectively. Rab1 is physiologically essential for autophagy and transport between endoplasmic reticulum and Golgi apparatus. Pathologically, Rab1 is implicated in human cancers, a neurodegenerative disease, cardiomyopathy, and bacteria-caused infectious diseases. We have performed structural analyses on Rab1 protein using a unique ensemble of clustering methods, including multi-step principal component analysis, non-negative matrix factorization, and independent component analysis, to better identify representative Rab1 proteins than the application of a single clustering method alone does. We then used the identified representative Rab1 structures, resolved in multiple ligand states, to map their known and novel binding sites. We report here at least a novel binding site on Rab1, involving Rab1-specific residues that could be further explored for the rational design and development of investigative probes and/or therapeutic small molecules against the Rab1 protein. Proteins 2017; 85:859–871.",
    keywords = "allosteric site, binding site, drug design, GTPase, molecular recognition, protein flexibility, structural bioinformatics, structural clustering",
    author = "Suryani Lukman and Nguyen, {Minh N.} and Kelvin Sim and Jeremy Teo",
    year = "2017",
    month = "5",
    day = "1",
    doi = "10.1002/prot.25254",
    language = "English (US)",
    volume = "85",
    pages = "859--871",
    journal = "Proteins: Structure, Function and Genetics",
    issn = "0887-3585",
    publisher = "Wiley-Liss Inc.",
    number = "5",

    }

    TY - JOUR

    T1 - Discovery of Rab1 binding sites using an ensemble of clustering methods

    AU - Lukman, Suryani

    AU - Nguyen, Minh N.

    AU - Sim, Kelvin

    AU - Teo, Jeremy

    PY - 2017/5/1

    Y1 - 2017/5/1

    N2 - Targeting non-native-ligand binding sites for potential investigative and therapeutic applications is an attractive strategy in proteins that share common native ligands, as in Rab1 protein. Rab1 is a subfamily member of Rab proteins, which are members of Ras GTPase superfamily. All Ras GTPase superfamily members bind to native ligands GTP and GDP, that switch on and off the proteins, respectively. Rab1 is physiologically essential for autophagy and transport between endoplasmic reticulum and Golgi apparatus. Pathologically, Rab1 is implicated in human cancers, a neurodegenerative disease, cardiomyopathy, and bacteria-caused infectious diseases. We have performed structural analyses on Rab1 protein using a unique ensemble of clustering methods, including multi-step principal component analysis, non-negative matrix factorization, and independent component analysis, to better identify representative Rab1 proteins than the application of a single clustering method alone does. We then used the identified representative Rab1 structures, resolved in multiple ligand states, to map their known and novel binding sites. We report here at least a novel binding site on Rab1, involving Rab1-specific residues that could be further explored for the rational design and development of investigative probes and/or therapeutic small molecules against the Rab1 protein. Proteins 2017; 85:859–871.

    AB - Targeting non-native-ligand binding sites for potential investigative and therapeutic applications is an attractive strategy in proteins that share common native ligands, as in Rab1 protein. Rab1 is a subfamily member of Rab proteins, which are members of Ras GTPase superfamily. All Ras GTPase superfamily members bind to native ligands GTP and GDP, that switch on and off the proteins, respectively. Rab1 is physiologically essential for autophagy and transport between endoplasmic reticulum and Golgi apparatus. Pathologically, Rab1 is implicated in human cancers, a neurodegenerative disease, cardiomyopathy, and bacteria-caused infectious diseases. We have performed structural analyses on Rab1 protein using a unique ensemble of clustering methods, including multi-step principal component analysis, non-negative matrix factorization, and independent component analysis, to better identify representative Rab1 proteins than the application of a single clustering method alone does. We then used the identified representative Rab1 structures, resolved in multiple ligand states, to map their known and novel binding sites. We report here at least a novel binding site on Rab1, involving Rab1-specific residues that could be further explored for the rational design and development of investigative probes and/or therapeutic small molecules against the Rab1 protein. Proteins 2017; 85:859–871.

    KW - allosteric site

    KW - binding site

    KW - drug design

    KW - GTPase

    KW - molecular recognition

    KW - protein flexibility

    KW - structural bioinformatics

    KW - structural clustering

    UR - http://www.scopus.com/inward/record.url?scp=85013243956&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85013243956&partnerID=8YFLogxK

    U2 - 10.1002/prot.25254

    DO - 10.1002/prot.25254

    M3 - Article

    VL - 85

    SP - 859

    EP - 871

    JO - Proteins: Structure, Function and Genetics

    JF - Proteins: Structure, Function and Genetics

    SN - 0887-3585

    IS - 5

    ER -