7lxu

Structure of Plasmodium falciparum 20S proteasome with bound MPI-5Structure of Plasmodium falciparum 20S proteasome with bound MPI-5

Structural highlights 7lxu is a 20 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8IAR3_PLAF7 Publication Abstract from PubMed The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) beta5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax 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 P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S 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 P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.,Xie SC, Metcalfe RD, Mizutani H, Puhalovich T, Hanssen E, Morton CJ, Du Y, Dogovski C, Huang SC, Ciavarri J, Hales P, Griffin RJ, Cohen LH, Chuang BC, Wittlin S, Deni I, Yeo T, Ward KE, Barry DC, Liu B, Gillett DL, Crespo-Fernandez BF, Ottilie S, Mittal N, Churchyard A, Ferguson D, Aguiar ACC, Guido RVC, Baum J, Hanson KK, Winzeler EA, Gamo FJ, Fidock DA, Baud D, Parker MW, Brand S, Dick LR, Griffin MDW, Gould AE, Tilley L Proc Natl Acad Sci U S A. 2021 Sep 28;118(39):e2107213118. doi: , 10.1073/pnas.2107213118. PMID:34548400 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

spinqualitylabelsall models 7lxu, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image