6LOX

Crystal Structure of human glutaminase with macrocyclic inhibitor

Summary for 6LOX

• Entry DOI: 10.2210/pdb6lox/pdb
• Descriptor: Glutaminase kidney isoform, mitochondrial, (E)-15,22-Dioxa-4,11-diaza-5(2,5)-thiadiazola-10(3,6)-pyridazina-1,14(1,3)-dibenzenacyclodocosaphan-18-ene-3,12-dione (3 entities in total)
• Functional Keywords: protein-inhibitor complex, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 236949.40

Authors

Bian, J.,Li, Z.,Xu, X.,Wang, J.,Li, L. (deposition date: 2020-01-07, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

Xu, X.,Wang, J.,Wang, M.,Yuan, X.,Li, L.,Zhang, C.,Huang, H.,Jing, T.,Wang, C.,Tong, C.,Zhou, L.,Meng, Y.,Xu, P.,Kou, J.,Qiu, Z.,Li, Z.,Bian, J.
Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site.
J.Med.Chem., 64:4588-4611, 2021

PubMed Abstract: The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule () was identified with robust GLS1 inhibitory activity (IC = 6 nM) and high GLS1 binding affinity (SPR, = 24 nM; ITC, = 37 nM). The X-ray crystal structure of the -GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, exhibited a similar antitumor activity as . This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.

PubMed: 33792311
DOI: 10.1021/acs.jmedchem.0c02044

Experimental method

X-RAY DIFFRACTION (3.2 Å)