PDBsum entry 5eqg

Transport protein/inhibitor

PDB id: 5eqg

Contents

Protein chain

447 a.a.

Ligands

5RE

PDB id:

5eqg

Name:

Transport protein/inhibitor

Title:

Human glut1 in complex with inhibitor (2~{s})-3-(4-fluorophenyl)-2-[2- (3-hydroxyphenyl)ethanoylamino]-~{n}-[(1~{s})-1- phenylethyl]propanamide

Structure:

Solute carrier family 2, facilitated glucose transporter member 1. Chain: a. Synonym: glucose transporter type 1, erythrocyte/brain, glut-1, hepg2 glucose transporter. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: slc2a1, glut1. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.

Resolution:

2.90Å R-factor: 0.238 R-free: 0.281

Authors:

K.Kapoor,J.Finer-Moore,B.P.Pedersen,L.Caboni,A.B.Waight,R.Hillig, P.Bringmann,I.Heisler,T.Muller,H.Siebeneicher,R.M.Stroud

Key ref:

K.Kapoor et al. (2016). Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides. Proc Natl Acad Sci U S A, 113, 4711-4716. PubMed id: 27078104 DOI: 10.1073/pnas.1603735113

Date:

12-Nov-15 Release date: 13-Apr-16

Protein chain

P11166  (GTR1_HUMAN) -  Solute carrier family 2, facilitated glucose transporter member 1 from Homo sapiens

Seq: 492 a.a.

Struc: 447 a.a.

DOI no: 10.1073/pnas.1603735113

Proc Natl Acad Sci U S A 113:4711-4716 (2016)

PubMed id: 27078104

Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides.

K.Kapoor, J.S.Finer-Moore, B.P.Pedersen, L.Caboni, A.Waight, R.C.Hillig, P.Bringmann, I.Heisler, T.Müller, H.Siebeneicher, R.M.Stroud.

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.