View source for 10kv


==Structure of hNSP4 bound to MCP4 at 2.75 A resolution==
<StructureSection load='10kv' size='340' side='right'caption='[[10kv]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[10kv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=10KV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=10KV 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]] 2.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=10kv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=10kv OCA], [https://pdbe.org/10kv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=10kv RCSB], [https://www.ebi.ac.uk/pdbsum/10kv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=10kv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PRS57_HUMAN PRS57_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Neutrophil serine protease 4 (NSP4) is the most ancient member of the NSP family, which includes neutrophil elastase, proteinase 3 and cathepsin G, but is unique in its strong preference for cleavage after an arginine residue. NSP4 is highly expressed in myeloid precursor cells and regulates the levels of vasoactive histamine during mast cell maturation. Neutrophils store active NSP4 in azurophilic granules, but its function in neutrophil biology remains unknown. To advance the understanding of NSP4's biological role, we aimed to generate potent and selective inhibitors by using large mRNA-displayed libraries each encoding up to 10(13) unique macrocyclic peptides (MCPs) containing both natural and non-natural amino acids. Library screening yielded six MCPs, which strongly inhibited the activity of recombinant and endogenous cell-derived NSP4, but did not inhibit 13 structurally related proteases. In agreement with biochemical studies with activity-based probes, crystal structures of the two most potent inhibitors MCP-3 and MCP-4 (K(D) = 6.5 nM and 1.0 nM, respectively) revealed that these MCPs bind to the NSP4 active site region. Remarkably, the two MCPs resembled the plant-derived sunflower trypsin inhibitor-1 in respect to ring conformation, substrate-like interaction with the active site and resistance to hydrolysis. Therefore, these de novo generated MCPs recapitulated the standard mechanism used by natural serine protease inhibitors. This study highlights the power of mRNA display technology to generate potent and highly selective protease inhibitors, such as the macrocyclic NSP4 inhibitors identified in this work, which serve as valuable tools to study the biological functions of this elusive protease.

Novel Macrocyclic Peptides as Potent and Selective Inhibitors of Human Neutrophil Serine Protease 4.,Tang W, Ultsch M, Adaligil E, Tombling B, Fleming S, Wei Y, Martinez OE, Song A, Di Lello P, Sudhamsu J, Cunningham CN, Kirchhofer D J Mol Biol. 2026 Jun 9;438(19):169894. doi: 10.1016/j.jmb.2026.169894. PMID:42264133<ref>PMID:42264133</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 10kv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Sudhamsu J]]
[[Category: Tang W]]
[[Category: Ultsch MH]]