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3rea

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3rea, resolution 2.00Å ()
Gene: HIV-1 Nef, nef (HIV-1 M:B_ARV2/SF2), HCK (Homo sapiens)
Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Related: 3reb, 3rbb, 1efn, 1avz, 2nef, 1qa5


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

HIV-1 Nef protein in complex with engineered Hck-SH3 domain

Publication Abstract from PubMed

Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as "wrapping Nef", is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors.

Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef., Breuer S, Schievink SI, Schulte A, Blankenfeldt W, Fackler OT, Geyer M, PLoS One. 2011;6(5):e20033. Epub 2011 May 20. PMID:021625496

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[HCK_HUMAN] Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.[1][2] Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.[3][4]

Function

[NEF_HV1A2] 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).[5][6][7][8][9][10] 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) (By similarity).[11][12][13][14][15][16] 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).[17][18][19][20][21][22] 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).[23][24][25][26][27][28] Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).[29][30][31][32][33][34] [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.[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]

About this Structure

3rea is a 4 chain structure with sequence from Hiv-1 m:b_arv2/sf2 and Homo sapiens. Full crystallographic information is available from OCA.

Reference

  1. Poincloux R, Al Saati T, Maridonneau-Parini I, Le Cabec V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane- and lysosome-associated isoforms. Eur J Cancer. 2009 Feb;45(3):321-7. doi: 10.1016/j.ejca.2008.11.020. Epub 2008, Dec 26. PMID:19114024 doi:10.1016/j.ejca.2008.11.020
  2. Pene-Dumitrescu T, Smithgall TE. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010 Jul 9;285(28):21446-57. doi: 10.1074/jbc.M109.090043. Epub 2010, May 7. PMID:20452982 doi:10.1074/jbc.M109.090043
  3. Poincloux R, Al Saati T, Maridonneau-Parini I, Le Cabec V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane- and lysosome-associated isoforms. Eur J Cancer. 2009 Feb;45(3):321-7. doi: 10.1016/j.ejca.2008.11.020. Epub 2008, Dec 26. PMID:19114024 doi:10.1016/j.ejca.2008.11.020
  4. Pene-Dumitrescu T, Smithgall TE. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010 Jul 9;285(28):21446-57. doi: 10.1074/jbc.M109.090043. Epub 2010, May 7. PMID:20452982 doi:10.1074/jbc.M109.090043
  5. Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
  6. Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
  7. Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
  8. Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
  9. Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
  10. Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
  11. Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
  12. Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
  13. Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
  14. Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
  15. Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
  16. Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
  17. Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
  18. Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
  19. Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
  20. Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
  21. Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
  22. Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
  23. Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
  24. Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
  25. Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
  26. Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
  27. Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
  28. Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
  29. Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
  30. Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
  31. Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
  32. Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
  33. Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
  34. Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
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  36. Durden DL, Kim HM, Calore B, Liu Y. The Fc gamma RI receptor signals through the activation of hck and MAP kinase. J Immunol. 1995 Apr 15;154(8):4039-47. PMID:7535819
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  38. Warmuth M, Bergmann M, Priess A, Hauslmann K, Emmerich B, Hallek M. The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J Biol Chem. 1997 Dec 26;272(52):33260-70. PMID:9407116
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  49. Paliwal P, Radha V, Swarup G. Regulation of p73 by Hck through kinase-dependent and independent mechanisms. BMC Mol Biol. 2007 May 30;8:45. PMID:17535448 doi:10.1186/1471-2199-8-45
  50. Hausherr A, Tavares R, Schaffer M, Obermeier A, Miksch C, Mitina O, Ellwart J, Hallek M, Krause G. Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases. Oncogene. 2007 Jul 26;26(34):4987-98. Epub 2007 Feb 19. PMID:17310994 doi:10.1038/sj.onc.1210306
  51. Poincloux R, Al Saati T, Maridonneau-Parini I, Le Cabec V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane- and lysosome-associated isoforms. Eur J Cancer. 2009 Feb;45(3):321-7. doi: 10.1016/j.ejca.2008.11.020. Epub 2008, Dec 26. PMID:19114024 doi:10.1016/j.ejca.2008.11.020
  52. Baruzzi A, Iacobucci I, Soverini S, Lowell CA, Martinelli G, Berton G. c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration. FEBS Lett. 2010 Jan 4;584(1):15-21. doi: 10.1016/j.febslet.2009.11.009. Epub . PMID:19903482 doi:10.1016/j.febslet.2009.11.009
  53. Pene-Dumitrescu T, Smithgall TE. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010 Jul 9;285(28):21446-57. doi: 10.1074/jbc.M109.090043. Epub 2010, May 7. PMID:20452982 doi:10.1074/jbc.M109.090043

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