Objectives:
The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective
tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards
aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes
the facilitative glucose transporter GLUT10. The molecules transported by and interacting with
GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the
substrate binding site of GLUT10 and the molecules interacting with this site.
Methods:
As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology
model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics
investigation were employed.
Results and Discussion:
Blind docking of nine reported potential in vitro substrates with this 3D homology
model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437,
TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520,
SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the
Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database
(HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10,
which were found to be involved directly or partially in ATS progression or different arterial disorders.
Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p.
Glu437Lys) is located in the predicted substrate binding site region.
Conclusion:
Virtual screening expands the possibility to explore more compounds that can interact
with GLUT10 and may aid in understanding the mechanisms leading to ATS.
The Role of the Conserved Glycines of ATP-binding Cassette Signature Motifs of MRP1 in the Communication between the Substrate-binding Site and the Catalytic Centers
