4XUI

Crystal structure analysis of cruzain bound to the no-covalent analog of WRR-483 (WRR-669)

Replaces:  4PI4

Summary for 4XUI

• Entry DOI: 10.2210/pdb4xui/pdb
• Related: 4PI3
• Descriptor: Cruzipain, N-[(2S)-5-(carbamimidamidooxy)-1-oxo-1-{[(1E,3S)-5-phenyl-1-(pyrimidin-2-ylsulfonyl)pent-1-en-3-yl]amino}pentan-2-yl]-4-methylpiperazine-1-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: cruzain, cysteine protease, covalent reversible inhibitor, chagas disease, trypanosoma cruzi, vinyl sulfone analog, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Trypanosoma cruzi
• Total number of polymer chains: 3
• Total formula weight: 70369.99

Authors

Tochowicz, A.,McKerrow, J.H. (deposition date: 2015-01-26, release date: 2015-03-11, Last modification date: 2024-11-13)

Primary citation

Jones, B.D.,Tochowicz, A.,Tang, Y.,Cameron, M.D.,McCall, L.I.,Hirata, K.,Siqueira-Neto, J.L.,Reed, S.L.,McKerrow, J.H.,Roush, W.R.
Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain.
Acs Med.Chem.Lett., 7:77-82, 2016

PubMed Abstract: A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cruzain inhibitors. Co-crystal structures of the oxyguanidine analogues WRR-666 (4) and WRR-669 (7) bound to cruzain demonstrated different binding interactions with the cysteine protease, depending on the aryl moiety of the P1' inhibitor subunit. Specifically, these data demonstrate that WRR-669 is bound noncovalently in the crystal structure. This represents a rare example of noncovalent inhibition of a cysteine protease by a vinyl sulfone inhibitor.

PubMed: 26819670
DOI: 10.1021/acsmedchemlett.5b00336

Experimental method

X-RAY DIFFRACTION (2.508 Å)