View source for 8slo


==Plasmodium falciparum M1 aminopeptidase bound to selective inhibitor MIPS2673==
<StructureSection load='8slo' size='340' side='right'caption='[[8slo]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8slo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SLO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SLO FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BYW:2-hydroxy-N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]-2-methylpropanamide'>BYW</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8slo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8slo OCA], [https://pdbe.org/8slo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8slo RCSB], [https://www.ebi.ac.uk/pdbsum/8slo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8slo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AMPN_PLAF7 AMPN_PLAF7] Displays aminopeptidase activity with a broad substrate specificity (PubMed:12166515, PubMed:19196988, PubMed:21659511, PubMed:21844374, PubMed:22359643, PubMed:23897806, PubMed:33536500, PubMed:34133730, PubMed:9879894). Preferentially, cleaves after Leu and Met, but cleaves also after Ala and Arg (PubMed:12166515, PubMed:21844374, PubMed:22359643, PubMed:33536500). Low activity towards Lys, Phe, Tyr, Trp, Gln, Ser and Gly and negligible activity towards Glu, Asp, Pro, Ile, Thr, Val, His and Asn (PubMed:22359643). Has dipeptidase activity (PubMed:21659511, PubMed:23897806). Plays a role in the terminal stages of host hemoglobin digestion by cleaving the N-terminal residue of small hemoglobin-derived oligopeptides (PubMed:21659511, PubMed:21844374, PubMed:34133730).<ref>PMID:12166515</ref> <ref>PMID:19196988</ref> <ref>PMID:21659511</ref> <ref>PMID:21844374</ref> <ref>PMID:22359643</ref> <ref>PMID:23897806</ref> <ref>PMID:33536500</ref> <ref>PMID:34133730</ref> <ref>PMID:9879894</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (PvA-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets PfA-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on PfA-M1 to within ~5 A of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.,Giannangelo C, Challis MP, Siddiqui G, Edgar R, Malcolm TR, Webb CT, Drinkwater N, Vinh N, Macraild C, Counihan N, Duffy S, Wittlin S, Devine SM, Avery VM, De Koning-Ward T, Scammells P, McGowan S, Creek DJ Elife. 2024 Jul 8;13:RP92990. doi: 10.7554/eLife.92990. PMID:38976500<ref>PMID:38976500</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8slo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum]]
[[Category: Drinkwater N]]
[[Category: McGowan SM]]