PDBsum entry 6ex8

Hydrolase

PDB id: 6ex8

Contents

Protein chains

217 a.a.

Ligands

C2K ×2

EDO ×17

Waters ×361

PDB id:

6ex8

Name:

Hydrolase

Title:

Crystal structure of rhodesain in complex with a macrolactam inhibitor

Structure:

Cysteine protease. Chain: a, b. Engineered: yes. Mutation: yes. Other_details: cathepsin l-like cysteine protease with a reversible oxidation (sulfenic acid) at its active-site cysteine (cys25)

Source:

Trypanosoma brucei rhodesiense. Organism_taxid: 31286. Gene: rhodesain. Expressed in: komagataella pastoris. Expression_system_taxid: 4922.

Resolution:

1.60Å R-factor: 0.138 R-free: 0.177

Authors:

U.Dietzel,C.Kisker

Key ref:

M.Giroud et al. (2018). 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. PubMed id: 29590750 DOI: 10.1021/acs.jmedchem.7b01869

Date:

07-Nov-17 Release date: 11-Apr-18

Protein chains

Q95PM0  (Q95PM0_TRYBR) -  Cysteine protease (Fragment) from Trypanosoma brucei rhodesiense

Seq: 450 a.a.

Struc: 217 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1021/acs.jmedchem.7b01869

J Med Chem 61:3350-3369 (2018)

PubMed id: 29590750

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

M.Giroud, U.Dietzel, L.Anselm, D.Banner, A.Kuglstatter, J.Benz, J.B.Blanc, D.Gaufreteau, H.Liu, X.Lin, A.Stich, B.Kuhn, F.Schuler, M.Kaiser, R.Brun, T.Schirmeister, C.Kisker, F.Diederich, W.Haap.

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_i < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC₅₀ < 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.