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Conformational Studies of Glucose Transporter 1 (GLUT1) as an Anticancer Drug Target
Suliman Almahmoud1, Xiaofang Wang2, Jonathan L Vennerstrom3
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA. suliman.almahmoud@unmc.edu.
Abstract:
Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein. To find out the most favorable GLUT 1 conformation for ligand binding, we ran systemic molecular docking studies for different conformations of GLUT1 using known GLUT1 inhibitors. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play critical roles in ligand binding to GLUT1. Our data suggests that conformational differences in these five amino acids in the different conformers of GLUT1 may be used to design ligands that inhibit GLUT1.
Insights
The inward-open conformation is preferred for glucose transporter 1 (GLUT1) binding. Key amino acid residues identified could guide the design of novel GLUT1 inhibitors for cancer therapy.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Glucose transporter 1 (GLUT1) is overexpressed in tumors, making it a key target for cancer therapy.
- GLUT1 facilitates glucose transport via conformational changes, switching between outward-open (OOP), occluded, and inward-open (IOP) states.
Purpose of the Study:
- To determine the preferred GLUT1 conformation for ligand binding using molecular docking.
- To identify critical amino acid residues involved in GLUT1-ligand interactions.
Main Methods:
- Systematic molecular docking studies were performed on different GLUT1 conformations.
- Known GLUT1 inhibitors were used as ligands in the docking simulations.
Main Results:
- The inward-open (IOP) conformation was identified as the preferred state for ligand binding.
- Residues Phe291, Phe379, Glu380, Trp388, and Trp412 were found to play critical roles in GLUT1-ligand interactions.
Conclusions:
- The IOP conformation is crucial for effective GLUT1 inhibition.
- Conformational variations in specific amino acids (Phe291, Phe379, Glu380, Trp388, Trp412) can be exploited for designing targeted GLUT1 inhibitors.
Related Concept Videos
01:27Glucose Transporters
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
01:20Conformity
01:55Secondary Active Transport
01:47Primary Active Transport
01:19Facilitated Transport
01:24Cellular Membranes and Drug Transport
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