5JYP

Allosteric inhibition of Kidney Isoform of Glutaminase

Summary for 5JYP

• Entry DOI: 10.2210/pdb5jyp/pdb
• Related: 5JYO
• Descriptor: Glutaminase kidney isoform, mitochondrial, 2-phenyl-~{N}-[5-[(1~{S},3~{S})-3-[5-(2-phenylethanoylamino)-1,3,4-thiadiazol-2-yl]cyclohexyl]-1,3,4-thiadiazol-2-yl]ethanamide (3 entities in total)
• Functional Keywords: kga, gac, allosteric inhibition, warburg effect, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37153.40

Authors

Ramachandran, S.,Sivaraman, J. (deposition date: 2016-05-15, release date: 2016-08-03, Last modification date: 2023-11-08)

Primary citation

Ramachandran, S.,Pan, C.Q.,Zimmermann, S.C.,Duvall, B.,Tsukamoto, T.,Low, B.C.,Sivaraman, J.
Structural basis for exploring the allosteric inhibition of human kidney type glutaminase.
Oncotarget, 7:57943-57954, 2016

PubMed Abstract: Cancer cells employ glutaminolysis to provide a source of intermediates for their upregulated biosynthetic needs. Glutaminase, which catalyzes the conversion of glutamine to glutamate, is gaining increasing attention as a potential drug target. Small-molecule inhibitors such as BPTES and CB-839, which target the allosteric site of glutaminase with high specificity, demonstrate immense promise as anti-tumor drugs. Here, we report the study of a new BPTES analog, N,N'-(5,5'-(trans-cyclohexane-1,3-diyl)bis(1,3,4-tiadiazole-5,2-diyl))bis(2-phenylacetamide) (trans-CBTBP), and compared its inhibitory effect against that of CB-839 and BPTES. We show that CB-839 has a 30- and 50-fold lower IC50 than trans-CBTBP and BPTES, respectively. To explore the structural basis for the differences in their inhibitory efficacy, we solved the complex structures of cKGA with 1S, 3S-CBTBP and CB-839. We found that CB-839 produces a greater degree of interaction with cKGA than 1S, 3S-CBTBP or BPTES. The results of this study will facilitate the rational design of new KGA inhibitors to better treat glutamine-addicted cancers.

PubMed: 27462863
DOI: 10.18632/oncotarget.10791

Experimental method

X-RAY DIFFRACTION (2.74 Å)