View source for 9zjc


==Crystal structure of MERS 3CL protease in complex with inhibitor IKR-I-52==
<StructureSection load='9zjc' size='340' side='right'caption='[[9zjc]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9zjc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Middle_East_respiratory_syndrome-related_coronavirus Middle East respiratory syndrome-related coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9ZJC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9ZJC 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1C2W:(2~{S})-4-methyl-2-[[(2~{S},4~{R})-4-methyl-2-oxidanylidene-3-(phenylmethyl)-1,3,2$l^{5}-oxazaphospholidin-2-yl]amino]-~{N}-[(2~{S})-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]pentanamide'>A1C2W</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=9zjc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9zjc OCA], [https://pdbe.org/9zjc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9zjc RCSB], [https://www.ebi.ac.uk/pdbsum/9zjc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9zjc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/R1A_MERS1 R1A_MERS1] The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products.[UniProtKB:P0C6X7]  Promotes the degradation of host mRNAs by inducing an endonucleolytic RNA cleavage in template mRNAs, and inhibits of host mRNA translation, a function that is separable from its RNA cleavage activity. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.<ref>PMID:26311885</ref>   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]<ref>PMID:25142582</ref>   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]. Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7][PROSITE-ProRule:PRU00772]  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]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Constant changes in SARS-CoV-2 in human populations as well as potential future spillovers from animal coronaviruses have provided the impetus for the development of additional direct-acting antivirals. We describe herein the discovery of a new class of broad-spectrum inhibitors of coronavirus 3C-like protease (3CLpro), a cysteine protease essential for viral replication and a validated drug target, that incorporate in their structure a 1,3,2-oxazaphospholidin-3-one scaffold. Inhibitors 1 and 2 potently inhibited SARS-CoV-2 3CLpro (IC(50) = 0.34 and 0.23 muM) and MERS-CoV 3CLpro (IC(50) = 0.12 and 0.09 muM), and displayed antiviral activity against SARS-CoV-2 (EC(50) = 60 and 50 nM) with low cytotoxicity (CC(50) &gt; 100 muM). Importantly, several of the synthesized compounds inhibited recombinant human cathepsin L with IC(50) values in the low nM to sub-nM range. Thus, the compounds can potentially exhibit high antiviral potency by abrogating viral entry via the inhibition of cathepsin L and viral replication by inhibition of 3CLpro. High resolution cocrystal structures were determined to elucidate the mechanism of action, identify the molecular determinants associated with binding, and to inform the optimization process.

Structure-guided design of broad-spectrum inhibitors of coronaviral proteases embodying a 1,3,2-oxazaphospholidin-3-one scaffold as a versatile design element.,Nguyen HN, Ranasinghe PS, Ilesinghe IKRS, Dampalla CS, Rathnayake AD, Liska Z, Jesri AM, Azmi Z, Nevonen DE, Kim Y, Ung AR, Taylor KE, Cooper A, Liu L, Battaile KP, Thurman HA, Gusachenko E, Lovell S, Groutas WC, Chang KO Eur J Med Chem. 2026 May 26;316:119002. doi: 10.1016/j.ejmech.2026.119002. PMID:42208369<ref>PMID:42208369</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9zjc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Middle East respiratory syndrome-related coronavirus]]
[[Category: Battaile KP]]
[[Category: Groutas WC]]
[[Category: Ilesinghe IKRS]]
[[Category: Lovell S]]
[[Category: Ung AR]]