 |
PDBsum entry 5eqg
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transport protein/inhibitor
|
PDB id
|
|
|
|
5eqg
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Mechanism of inhibition of human glucose transporter glut1 is conserved between cytochalasin b and phenylalanine amides.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2016,
113,
4711-4716.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
