5eqh
Human GLUT1 in complex with inhibitor (2~{S})-3-(2-bromophenyl)-2-[2-(4-methoxyphenyl)ethanoylamino]-~{N}-[(1~{S})-1-phenylethyl]propanamide
Structural highlights
DiseaseGTR1_HUMAN Hereditary cryohydrocytosis with reduced stomatin;Paroxysmal exertion-induced dyskinesia;Encephalopathy due to GLUT1 deficiency;Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity;Childhood absence epilepsy;Epilepsy with myoclonic-astatic seizures. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGTR1_HUMAN Facilitative glucose transporter. This isoform may be responsible for constitutive or basal glucose uptake. Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses. Publication Abstract from PubMedCancerous 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. Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides.,Kapoor K, Finer-Moore JS, Pedersen BP, Caboni L, Waight A, Hillig RC, Bringmann P, Heisler I, Muller T, Siebeneicher H, Stroud RM Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):4711-6. doi:, 10.1073/pnas.1603735113. Epub 2016 Apr 12. PMID:27078104[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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