title: Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides.
abstract: Cancerous cells have an acutely increased demand for energy, leading to increased levels of human glucose transporter 1 (hGLUT1). This up-regulation suggests hGLUT1 as a target for therapeutic inhibitors addressing a multitude of cancer types. Here, we present three inhibitor-bound, inward-open structures of WT-hGLUT1 crystallized with three different inhibitors: cytochalasin B, a nine-membered bicyclic ring fused to a 14-membered macrocycle, which has been described extensively in the literature of hGLUTs, and two previously undescribed Phe amide-derived inhibitors. Despite very different chemical backbones, all three compounds bind in the central cavity of the inward-open state of hGLUT1, and all binding sites overlap the glucose-binding site. The inhibitory action of the compounds was determined for hGLUT family members, hGLUT1-4, using cell-based assays, and compared with homology models for these hGLUT members. This comparison uncovered a probable basis for the observed differences in inhibition between family members. We pinpoint regions of the hGLUT proteins that can be targeted to achieve isoform selectivity, and show that these same regions are used for inhibitors with very distinct structural backbones. The inhibitor cocomplex structures of hGLUT1 provide an important structural insight for the design of more selective inhibitors for hGLUTs and hGLUT1 in particular.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158;
authors.forename: Khyati
authors.initials: K
authors.lastname: Kapoor
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158;
authors.forename: Janet S
authors.initials: JS
authors.lastname: Finer-Moore
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark;
authors.forename: Bjørn P
authors.initials: BP
authors.lastname: Pedersen
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158;
authors.forename: Laura
authors.initials: L
authors.lastname: Caboni
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158;
authors.forename: Andrew
authors.initials: A
authors.lastname: Waight
authors.affiliation: Bayer Pharma AG, Drug Discovery, 13353 Berlin, Germany;
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
authors.affiliation: Bayer Pharmaceuticals, Biologics Research, San Francisco, CA 94158;
authors.forename: Peter
authors.initials: P
authors.lastname: Bringmann
authors.affiliation: Bayer Pharma AG, Drug Discovery, 42096 Wuppertal, Germany.
authors.forename: Iring
authors.initials: I
authors.lastname: Heisler
authors.affiliation: Bayer Pharma AG, Drug Discovery, 42096 Wuppertal, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Bayer Pharma AG, Drug Discovery, 13353 Berlin, Germany;
authors.forename: Holger
authors.initials: H
authors.lastname: Siebeneicher
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; stroud@msg.ucsf.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stroud
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D017124:Conserved Sequence; D003572:Cytochalasins / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D003572:Cytochalasins; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; C031218:cytochalasin A; D010649:Phenylalanine; C020457:phenylalanine amide; D005947:Glucose
keywords: GLUT inhibitor; X-ray structure; cytochalasin B; glucose facilitator; human MFS transporter