View source for 13ni


==PanDDA analysis group deposition -- Crystal structure of PLpro-C111S in complex with Fr12139==
<StructureSection load='13ni' size='340' side='right'caption='[[13ni]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[13ni]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=13NI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=13NI 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]] 1.94&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F2L:~{N}-[2,6-bis(fluoranyl)phenyl]ethanamide'>F2L</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</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=13ni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=13ni OCA], [https://pdbe.org/13ni PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=13ni RCSB], [https://www.ebi.ac.uk/pdbsum/13ni PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=13ni ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/R1AB_SARS2 R1AB_SARS2] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7]  Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7]  May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7]  Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7]  Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7]  Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291). Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]<ref>PMID:32198291</ref>   Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7]  Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7]  Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7]  May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7]  Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7]  Responsible for replication and transcription of the viral RNA genome.[UniProtKB:P0C6X7]  Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[UniProtKB:P0C6X7]  Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens.[UniProtKB:P0C6X7]  Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[UniProtKB:P0C6X7]  Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[UniProtKB:P0C6X7]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The COVID-19 pandemic has highlighted the need to develop broad-spectrum antiviral therapeutics targeting rapidly evolving coronaviruses. This research focuses on SARS-CoV-2 PL(pro), a conserved viral protease that plays dual roles in viral polyprotein processing and host immune suppression. Using an integrated fragment-based drug discovery (FBDD) approach that combines high-throughput X-ray crystallography and biochemical assays, we systematically screened a diverse library of 800 fragment compounds. Structural characterization identified 129 validated binders occupying 12 distinct binding sites on PL(pro). Remarkably, two fragments demonstrated potent micromolar inhibitory activity. Fr12895 inhibited SARS-CoV-2 PL(pro) protease activity (IC(50) = 8.013 muM), as measured using the fluorogenic substrate RLRGG-AMC, while Fr12338 showed inhibition against PL(pro) deISGylase activity (IC(50) = 4.5 muM), as determined with the substrate Ac-ISG15prox-Rh110MP. This provides a case for directly obtaining micromolar-active compounds through crystallographic fragment screening of a small number of random compounds. Detailed structural analysis revealed these fragments engage key functional regions including the blocking loop 2 (BL2) and ubiquitin/ISG15 binding interface through extensive hydrogen-bond networks and hydrophobic interactions. Our study reveals novel micromolar active inhibitors and druggable sites of SARS-CoV-2 PL(pro) by crystallographic fragment screening, provides crucial scaffold and a structural roadmap for developing broad-spectrum antivirals against coronaviruses.

Crystallographic fragment screening discovers novel micromolar active inhibitors and druggable hotspots of SARS-CoV-2 PL(pro).,Wang WW, Huang LQ, Xu Q, Zhu ZM, Li M, Zhou H, Han TL, Zheng SH, Li J, Wang QS, Yu F Int J Biol Macromol. 2026 Feb 2;347:150689. doi: 10.1016/j.ijbiomac.2026.150689. PMID:41638277<ref>PMID:41638277</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 13ni" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Han T]]
[[Category: Huang L]]
[[Category: Li M]]
[[Category: Wang Q]]
[[Category: Wang W]]
[[Category: Xu Q]]
[[Category: Yu F]]
[[Category: Zheng S]]
[[Category: Zhou H]]
[[Category: Zhu Z]]