1efn

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<StructureSection load='1efn' size='340' side='right'caption='[[1efn]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
<StructureSection load='1efn' size='340' side='right'caption='[[1efn]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[1efn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/9hiv1 9hiv1] and [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EFN FirstGlance]. <br>
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<table><tr><td colspan='2'>[[1efn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EFN FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PBM:TRIMETHYL+LEAD+ION'>PBM</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HIV-1 NEF ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), HIV-1 NEF ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PBM:TRIMETHYL+LEAD+ION'>PBM</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Transferase Transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1efn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1efn OCA], [https://pdbe.org/1efn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1efn RCSB], [https://www.ebi.ac.uk/pdbsum/1efn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1efn ProSAT]</span></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=1efn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1efn OCA], [https://pdbe.org/1efn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1efn RCSB], [https://www.ebi.ac.uk/pdbsum/1efn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1efn ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/FYN_HUMAN FYN_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1.<ref>PMID:7822789</ref> <ref>PMID:7568038</ref> <ref>PMID:11005864</ref> <ref>PMID:11162638</ref> <ref>PMID:11536198</ref> <ref>PMID:12788081</ref> <ref>PMID:12640114</ref> <ref>PMID:14761972</ref> <ref>PMID:15557120</ref> <ref>PMID:14707117</ref> <ref>PMID:15536091</ref> <ref>PMID:16387660</ref> <ref>PMID:16841086</ref> <ref>PMID:17194753</ref> <ref>PMID:18056706</ref> <ref>PMID:18258597</ref> <ref>PMID:19179337</ref> <ref>PMID:19652227</ref> <ref>PMID:20100835</ref> [[https://www.uniprot.org/uniprot/NEF_HV1BR NEF_HV1BR]] Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocytes function and down-regulates immunity surface molecules in order to evade host defense and increase viral infectivity. Alters the functionality of other immunity cells, like dendritic cells, monocytes/macrophages and NK cells. One of the earliest and most abundantly expressed viral proteins (By similarity).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref> In infected CD4(+) T-lymphocytes, down-regulates the surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates internalization and degradation of host CD4 through the interaction of with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin adapter protein complex 2), internalization through clathrin coated pits, and subsequent transport to endosomes and lysosomes for degradation. Diverts host MHC-I molecules to the trans-Golgi network-associated endosomal compartments by an endocytic pathway to finally target them for degradation. MHC-I down-regulation may involve AP-1 (clathrin adapter protein complex 1) or possibly Src family kinase-ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected cells are masked for immune recognition by cytotoxic T-lymphocytes. Decreasing the number of immune receptors also prevents reinfection by more HIV particles (superinfection).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref> Bypasses host T-cell signaling by inducing a transcriptional program nearly identical to that of anti-CD3 cell activation. Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL). Increasing surface FasL molecules and decreasing surface MHC-I molecules on infected CD4(+) cells send attacking cytotoxic CD8+ T-lymphocytes into apoptosis (By similarity).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref> Plays a role in optimizing the host cell environment for viral replication without causing cell death by apoptosis. Protects the infected cells from apoptosis in order to keep them alive until the next virus generation is ready to strike. Inhibits the Fas and TNFR-mediated death signals by blocking MAP3K5. Interacts and decreases the half-life of p53, protecting the infected cell against p53-mediated apoptosis. Inhibits the apoptotic signals regulated by the Bcl-2 family proteins through the formation of a Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and induces phosphorylation of Bad (By similarity).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref> Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).<ref>PMID:8151761</ref> <ref>PMID:8124721</ref> <ref>PMID:10684310</ref> <ref>PMID:11070003</ref> <ref>PMID:11285224</ref> <ref>PMID:11298454</ref> <ref>PMID:11861836</ref> <ref>PMID:14617802</ref> <ref>PMID:15854903</ref> <ref>PMID:16928758</ref> <ref>PMID:18005690</ref>
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[https://www.uniprot.org/uniprot/FYN_HUMAN FYN_HUMAN] Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1.<ref>PMID:7822789</ref> <ref>PMID:7568038</ref> <ref>PMID:11005864</ref> <ref>PMID:11162638</ref> <ref>PMID:11536198</ref> <ref>PMID:12788081</ref> <ref>PMID:12640114</ref> <ref>PMID:14761972</ref> <ref>PMID:15557120</ref> <ref>PMID:14707117</ref> <ref>PMID:15536091</ref> <ref>PMID:16387660</ref> <ref>PMID:16841086</ref> <ref>PMID:17194753</ref> <ref>PMID:18056706</ref> <ref>PMID:18258597</ref> <ref>PMID:19179337</ref> <ref>PMID:19652227</ref> <ref>PMID:20100835</ref>
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1efn ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1efn ConSurf].
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<div style="background-color:#fffaf0;">
 
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== Publication Abstract from PubMed ==
 
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The crystal structure of the conserved core of HIV-1 Nef has been determined in complex with the SH3 domain of a mutant Fyn tyrosine kinase (a single amino acid substitution, Arg-96 to isoleucine), to which Nef binds tightly. The conserved PxxP sequence motif of Nef, known to be important for optimal viral replication, is part of a polyproline type II helix that engages the SH3 domain in a manner resembling closely the interaction of isolated peptides with SH3 domains. The Nef-SH3 structure also reveals how high affinity and specificity in the SH3 interaction is achieved by the presentation of the PxxP motif within the context of the folded structure of Nef.
 
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Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain.,Lee CH, Saksela K, Mirza UA, Chait BT, Kuriyan J Cell. 1996 Jun 14;85(6):931-42. PMID:8681387<ref>PMID:8681387</ref>
 
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
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</div>
 
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<div class="pdbe-citations 1efn" style="background-color:#fffaf0;"></div>
 
==See Also==
==See Also==
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*[[Protein Nef|Protein Nef]]
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*[[Protein Nef 3D structures|Protein Nef 3D structures]]
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
== References ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Transferase]]
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[[Category: Kuriyan J]]
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[[Category: Kuriyan, J]]
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[[Category: Lee C-H]]
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[[Category: Lee, C H]]
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[[Category: Aid]]
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[[Category: Atp-binding]]
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[[Category: Gtp-binding]]
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[[Category: Myristylation]]
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[[Category: Phosphorylation]]
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[[Category: Ppii helix]]
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[[Category: Proto-oncogene]]
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[[Category: Pxxp motif]]
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[[Category: Sh2 domain]]
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[[Category: Sh3 domain]]
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[[Category: Tyrosine-protein kinase]]
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Current revision

HIV-1 NEF PROTEIN IN COMPLEX WITH R96I MUTANT FYN SH3 DOMAIN

PDB ID 1efn

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