View source for 4orz


==HIV-1 Nef protein in complex with single domain antibody sdAb19 and an engineered Hck SH3 domain==
<StructureSection load='4orz' size='340' side='right'caption='[[4orz]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4orz]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/HIV-1_M:B_ARV2/SF2 HIV-1 M:B_ARV2/SF2], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ORZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ORZ 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&#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=4orz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4orz OCA], [https://pdbe.org/4orz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4orz RCSB], [https://www.ebi.ac.uk/pdbsum/4orz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4orz ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HCK_HUMAN HCK_HUMAN] Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.<ref>PMID:19114024</ref> <ref>PMID:20452982</ref>   Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.<ref>PMID:19114024</ref> <ref>PMID:20452982</ref> 
== Function ==
[https://www.uniprot.org/uniprot/HCK_HUMAN HCK_HUMAN] Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.<ref>PMID:8132624</ref> <ref>PMID:7535819</ref> <ref>PMID:9406996</ref> <ref>PMID:9407116</ref> <ref>PMID:10092522</ref> <ref>PMID:10779760</ref> <ref>PMID:10973280</ref> <ref>PMID:12411494</ref> <ref>PMID:11741929</ref> <ref>PMID:11904303</ref> <ref>PMID:11896602</ref> <ref>PMID:15010462</ref> <ref>PMID:15952790</ref> <ref>PMID:15998323</ref> <ref>PMID:17535448</ref> <ref>PMID:17310994</ref> <ref>PMID:19114024</ref> <ref>PMID:19903482</ref> <ref>PMID:20452982</ref> 
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== Publication Abstract from PubMed ==
BACKGROUND: The HIV-1 Nef protein is essential for AIDS pathogenesis by its interaction with host cell surface receptors and signaling factors. Despite its critical role as a virulence factor Nef is not targeted by current antiviral strategies. RESULTS: We have determined the crystal structure of the complex formed by a camelid single-domain antibody fragment, termed sdAb19, bound to HIV-1 Nef together with a stabilizing SH3 domain. sdAb19 forms a stoichiometric 1:1 complex with Nef and binds to a conformationally conserved surface at the C-terminus of Nef that overlaps with functionally important interaction sites involved in Nef-induced perturbations of signaling and trafficking pathways. The antibody fragment binds Nef with low nanomolar affinity, which could be attenuated to micromolar affinity range by site-directed mutagenesis of key interaction residues in sdAb19. Fusion of the SH3 domain to sdAb19, termed Neffin, leads to a significantly increased affinity for Nef and formation of a stoichiometric 2:2 Nef-Neffin complex. The 19 kDa Neffin protein inhibits all functions of Nef as CD4 and MHC-I downregulation, association with Pak2, and the increase in virus infectivity and replication. CONCLUSIONS: Together, sdAb19 and Neffin thus represent efficient tools for the rational development of antiviral strategies against HIV-1 Nef.

Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody.,Lulf S, Matz J, Rouyez MC, Jarviluoma A, Saksela K, Benichou S, Geyer M Retrovirology. 2014 Mar 13;11(1):24. doi: 10.1186/1742-4690-11-24. PMID:24620746<ref>PMID:24620746</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 4orz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Antibody 3D structures|Antibody 3D structures]]
*[[Protein Nef|Protein Nef]]
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
*[[3D structures of non-human antibody|3D structures of non-human antibody]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: HIV-1 M:B_ARV2/SF2]]
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Geyer M]]
[[Category: Lulf S]]