View source for 7rfz


==Importin alpha 2 in complex with MERS ORF4B NLS peptide==
<StructureSection load='7rfz' size='340' side='right'caption='[[7rfz]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rfz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Middle_East_respiratory_syndrome-related_coronavirus Middle East respiratory syndrome-related coronavirus] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RFZ 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]] 1.95&#8491;</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=7rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rfz OCA], [https://pdbe.org/7rfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rfz RCSB], [https://www.ebi.ac.uk/pdbsum/7rfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rfz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IMA1_MOUSE IMA1_MOUSE] Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
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== Publication Abstract from PubMed ==
The MERS coronavirus (MERS-CoV) is a highly pathogenic, emerging virus that produces accessory proteins to antagonize the host innate immune response. The MERS-CoV ORF4b protein has been shown to bind preferentially to the nuclear import adapter IMPalpha3 in infected cells, thereby inhibiting NF-kappaB-dependent innate immune responses. Here, we report high-resolution structures of ORF4b bound to two distinct IMPalpha family members. Each exhibit highly similar binding mechanisms that, in both cases, lack a prototypical Lys bound at their P2 site. Mutations within the NLS region dramatically alter the mechanism of binding, which reverts to the canonical P2 Lys binding mechanism. Mutational studies confirm that the novel binding mechanism is important for its nuclear import, IMPalpha interaction, and inhibition of innate immune signaling pathways. In parallel, we determined structures of the nuclear binding domain of NF-kappaB component p50 bound to both IMPalpha2 and alpha3, demonstrating that p50 overlaps with the ORF4b binding sites, suggesting a basis for inhibition. Our results provide a detailed structural basis that explains how a virus can target the IMPalpha nuclear import adapter to impair immunity, and illustrate how small mutations in ORF4b, like those found in closely related coronaviruses such as HKU5, change the IMPalpha binding mechanism.

MERS-CoV ORF4b employs an unusual binding mechanism to target IMPalpha and block innate immunity.,Munasinghe TS, Edwards MR, Tsimbalyuk S, Vogel OA, Smith KM, Stewart M, Foster JK, Bosence LA, Aragao D, Roby JA, Basler CF, Forwood JK Nat Commun. 2022 Mar 25;13(1):1604. doi: 10.1038/s41467-022-28851-2. PMID:35338144<ref>PMID:35338144</ref>

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

==See Also==
*[[Importin 3D structures|Importin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Middle East respiratory syndrome-related coronavirus]]
[[Category: Mus musculus]]
[[Category: Aragao D]]
[[Category: Forwood JK]]
[[Category: Munasinghe TS]]
[[Category: Roby JA]]
[[Category: Tsimbalyuk S]]