6QM8

Leishmania tarentolae proteasome 20S subunit apo structure

Summary for 6QM8

• Entry DOI: 10.2210/pdb6qm8/pdb
• EMDB information: 4591
• Descriptor: Proteasome alpha1 chain, Proteasome beta3 chain, Proteasome beta4 chain, ... (14 entities in total)
• Functional Keywords: proteasome 20s subunit, hydrolase
• Biological source: Leishmania tarentolae; More
• Total number of polymer chains: 28
• Total formula weight: 847844.50

Authors

Rowland, P.,Goswami, P. (deposition date: 2019-02-01, release date: 2019-04-17, Last modification date: 2024-11-06)

Primary citation

Wyllie, S.,Brand, S.,Thomas, M.,De Rycker, M.,Chung, C.W.,Pena, I.,Bingham, R.P.,Bueren-Calabuig, J.A.,Cantizani, J.,Cebrian, D.,Craggs, P.D.,Ferguson, L.,Goswami, P.,Hobrath, J.,Howe, J.,Jeacock, L.,Ko, E.J.,Korczynska, J.,MacLean, L.,Manthri, S.,Martinez, M.S.,Mata-Cantero, L.,Moniz, S.,Nuhs, A.,Osuna-Cabello, M.,Pinto, E.,Riley, J.,Robinson, S.,Rowland, P.,Simeons, F.R.C.,Shishikura, Y.,Spinks, D.,Stojanovski, L.,Thomas, J.,Thompson, S.,Viayna Gaza, E.,Wall, R.J.,Zuccotto, F.,Horn, D.,Ferguson, M.A.J.,Fairlamb, A.H.,Fiandor, J.M.,Martin, J.,Gray, D.W.,Miles, T.J.,Gilbert, I.H.,Read, K.D.,Marco, M.,Wyatt, P.G.
Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.
Proc.Natl.Acad.Sci.USA, 116:9318-9323, 2019

PubMed Abstract: Visceral leishmaniasis (VL), caused by the protozoan parasites and , is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant and isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the proteasome. High-resolution cryo-EM structures of apo and compound 8-bound 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

PubMed: 30962368
DOI: 10.1073/pnas.1820175116

Experimental method

ELECTRON MICROSCOPY (3.3 Å)