6TD5

Leishmania tarentolae proteasome 20S subunit complexed with LXE408 and bortezomib

Summary for 6TD5

• Entry DOI: 10.2210/pdb6td5/pdb
• EMDB information: 10463
• Descriptor: Proteasome subunit alpha type, Proteasome subunit beta, Proteasome subunit family protein, ... (16 entities in total)
• Functional Keywords: proteasome complex, inhibitor, peptidase, hydrolase
• Biological source: Leishmania donovani; More
• Total number of polymer chains: 28
• Total formula weight: 810599.43

Authors

Srinivas, H. (deposition date: 2019-11-07, release date: 2020-08-26, Last modification date: 2020-10-21)

Primary citation

Nagle, A.,Biggart, A.,Be, C.,Srinivas, H.,Hein, A.,Caridha, D.,Sciotti, R.J.,Pybus, B.,Kreishman-Deitrick, M.,Bursulaya, B.,Lai, Y.H.,Gao, M.Y.,Liang, F.,Mathison, C.J.N.,Liu, X.,Yeh, V.,Smith, J.,Lerario, I.,Xie, Y.,Chianelli, D.,Gibney, M.,Berman, A.,Chen, Y.L.,Jiricek, J.,Davis, L.C.,Liu, X.,Ballard, J.,Khare, S.,Eggimann, F.K.,Luneau, A.,Groessl, T.,Shapiro, M.,Richmond, W.,Johnson, K.,Rudewicz, P.J.,Rao, S.P.S.,Thompson, C.,Tuntland, T.,Spraggon, G.,Glynne, R.J.,Supek, F.,Wiesmann, C.,Molteni, V.
Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.
J.Med.Chem., 63:10773-10781, 2020

PubMed Abstract: Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.

PubMed: 32667203
DOI: 10.1021/acs.jmedchem.0c00499

Experimental method

ELECTRON MICROSCOPY (3.2 Å)