Abstract
Rab11 is an important protein subfamily in the RabGTPase family. These proteins physiologically function as key regulators of intracellular membrane trafficking processes. Pathologically, Rab11 proteins are implicated in many diseases including cancers, neurodegenerative diseases and type 2 diabetes. Although they are medically important, no previous study has found Rab11 allosteric binding sites where potential drug candidates can bind to. In this study, by employing multiple clustering approaches integrating principal component analysis, independent component analysis and locally linear embedding, we performed structural analyses of Rab11 and identified eight representative structures. Using these representatives to perform binding site mapping and virtual screening, we identified two novel binding sites in Rab11 and small molecules that can preferentially bind to different conformations of these sites with high affinities. After identifying the binding sites and the residue interaction networks in the representatives, we computationally showed that these binding sites may allosterically regulate Rab11, as these sites communicate with switch 2 region that binds to GTP/GDP. These two allosteric binding sites in Rab11 are also similar to two allosteric pockets in Ras that we discovered previously.
Highlights
The largest member of the Ras superfamily is the Rab family of small GTPases, which contains almost 70 proteins
After identifying the binding sites and the residue interaction networks in the representatives, we computationally showed that these binding sites may allosterically regulate Rab11, as these sites communicate with switch 2 region that binds to GTP/ GDP
We examined the flexibility of Rab11 residues, identified potentially allosteric and/or transient binding sites, and screened potential binders to these sites
Summary
The largest member of the Ras superfamily is the Rab family of small GTPases, which contains almost 70 proteins. Rab proteins are important regulators of intracellular membrane trafficking, from the assembly of transport vesicles to their fusion with membranes. Rab proteins cycle between an inactive GDP-bound conformation and an active GTP-bound conformation. GTP-bound Rab proteins can recruit distinct set of downstream effectors to membranes; these effectors are essential for the formation, trafficking, tethering and fusion of transport vesicles. Rabs have been grouped into different subfamilies based on their distinct sequence motifs. The three members of Rab subfamily (Rab11a, Rab11b and Rab11c/Rab25) are closely related, evolutionary conserved, and differentially expressed. Rab11a is ubiquitously expressed, Rab11b is enriched in brain, heart, and testes [1], and Rab is only expressed in epithelial cells[2]. Rab11a and Rab11b proteins share 89% sequence identity, whereas Rab11a or Rab11b
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