7LXV

Structure of human 20S proteasome with bound MPI-5

Summary for 7LXV

• Entry DOI: 10.2210/pdb7lxv/pdb
• EMDB information: 23576
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-2, Proteasome subunit beta type-5, ... (15 entities in total)
• Functional Keywords: proteasome, plasmodium falciparum, malaria, drug, bortezomib, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 28
• Total formula weight: 718455.80

Authors

Metcalfe, R.D.,Morton, C.J.,Liu, B.,Xie, S.C.,Hanssen, E.,Leis, A.P.,Tilley, L.,Griffin, M.D.W. (deposition date: 2021-03-05, release date: 2021-09-22, Last modification date: 2025-05-14)

Primary citation

Xie, S.C.,Metcalfe, R.D.,Mizutani, H.,Puhalovich, T.,Hanssen, E.,Morton, C.J.,Du, Y.,Dogovski, C.,Huang, S.C.,Ciavarri, J.,Hales, P.,Griffin, R.J.,Cohen, L.H.,Chuang, B.C.,Wittlin, S.,Deni, I.,Yeo, T.,Ward, K.E.,Barry, D.C.,Liu, B.,Gillett, D.L.,Crespo-Fernandez, B.F.,Ottilie, S.,Mittal, N.,Churchyard, A.,Ferguson, D.,Aguiar, A.C.C.,Guido, R.V.C.,Baum, J.,Hanson, K.K.,Winzeler, E.A.,Gamo, F.J.,Fidock, D.A.,Baud, D.,Parker, M.W.,Brand, S.,Dick, L.R.,Griffin, M.D.W.,Gould, A.E.,Tilley, L.
Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of compared with a human cell line and exhibit high potency against field isolates of and They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to 20S than to human constitutive 20S (20Sc). Comparison of the cryo-electron microscopy (EM) structures of 20S and 20Sc in complex with MPI-5 and 20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in , underpinning the design of potent and selective antimalarial proteasome inhibitors.

PubMed: 34548400
DOI: 10.1073/pnas.2107213118

Experimental method

ELECTRON MICROSCOPY (3.4 Å)