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6F06

CATHEPSIN L IN COMPLEX WITH (3S,14E)-8-(azetidin-3-yl)-19-chloro-N-(1-cyanocyclopropyl)-5-oxo-12,17-dioxa-4-azatricyclo[16.2.2.06,11]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxamide

Summary for 6F06
Entry DOI10.2210/pdb6f06/pdb
Related6EZP 6EZX
DescriptorCathepsin L1, (3~{S},14~{E})-8-(azetidin-3-yl)-19-chloranyl-~{N}-(1-cyanocyclopropyl)-5-oxidanylidene-12,17-dioxa-4-azatricyclo[16.2.2.0^{6,11}]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxamide, ZINC ION, ... (5 entities in total)
Functional Keywordsprotease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase
Biological sourceHomo sapiens (Human)
Cellular locationLysosome: P07711
Total number of polymer chains2
Total formula weight50384.00
Authors
Kuglstatter, A.,Stihle, M. (deposition date: 2017-11-17, release date: 2018-04-11, Last modification date: 2018-05-09)
Primary citationGiroud, M.,Dietzel, U.,Anselm, L.,Banner, D.,Kuglstatter, A.,Benz, J.,Blanc, J.B.,Gaufreteau, D.,Liu, H.,Lin, X.,Stich, A.,Kuhn, B.,Schuler, F.,Kaiser, M.,Brun, R.,Schirmeister, T.,Kisker, C.,Diederich, F.,Haap, W.
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.
J. Med. Chem., 61:3350-3369, 2018
Cited by
PubMed Abstract: Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( K < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
PubMed: 29590750
DOI: 10.1021/acs.jmedchem.7b01869
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.02 Å)
Structure validation

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