7CRZ

Crystal structure of human glucose transporter GLUT3 bound with C3361

Summary for 7CRZ

• Entry DOI: 10.2210/pdb7crz/pdb
• Related: 6M2L
• Descriptor: Solute carrier family 2, facilitated glucose transporter member 3, (2S,3R,4S,5R,6R)-6-(hydroxymethyl)-4-undec-10-enoxy-oxane-2,3,5-triol, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (4 entities in total)
• Functional Keywords: mfs, hexose transporter, inhibitor, plasmodium falciparum, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 58946.16

Authors

Yuan, Y.Y.,Zhang, S.,Wang, N.,Jiang, X.,Yan, N. (deposition date: 2020-08-14, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

Huang, J.,Yuan, Y.,Zhao, N.,Pu, D.,Tang, Q.,Zhang, S.,Luo, S.,Yang, X.,Wang, N.,Xiao, Y.,Zhang, T.,Liu, Z.,Sakata-Kato, T.,Jiang, X.,Kato, N.,Yan, N.,Yin, H.
Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a "selective starvation" strategy by inhibiting hexose transporter 1 (PfHT1), the sole hexose transporter in , over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.

PubMed: 33402433
DOI: 10.1073/pnas.2017749118

Experimental method

X-RAY DIFFRACTION (2.3 Å)