View source for 7lxt


==Structure of Plasmodium falciparum 20S proteasome with bound bortezomib==
<StructureSection load='7lxt' size='340' side='right'caption='[[7lxt]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7lxt]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LXT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LXT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BO2:N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE'>BO2</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lxt OCA], [https://pdbe.org/7lxt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lxt RCSB], [https://www.ebi.ac.uk/pdbsum/7lxt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lxt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q8IAR3_PLAF7 Q8IAR3_PLAF7] 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:34548400</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lxt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Proteasome 3D structures|Proteasome 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum 3D7]]
[[Category: Griffin MDW]]
[[Category: Hanssen E]]
[[Category: Leis AP]]
[[Category: Liu B]]
[[Category: Metcalfe RD]]
[[Category: Morton CJ]]
[[Category: Tilley L]]
[[Category: Xie SC]]