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.
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