4U5W

Crystal Structure of HIV-1 Nef-SF2 Core Domain in Complex with the Src Family Kinase Hck SH3-SH2 Tandem Regulatory Domains

Summary for 4U5W

• Entry DOI: 10.2210/pdb4u5w/pdb
• Descriptor: Protein Nef, Tyrosine-protein kinase HCK, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (5 entities in total)
• Functional Keywords: hck, sh3-sh2 regulatory domains, sh3, sh2, src family kinase, sfk, hiv-1, nef, virus, protein-protein complex, nef-hck complex, viral protein-transferase complex, viral protein/transferase
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Total number of polymer chains: 4
• Total formula weight: 77786.27

Authors

Alvarado, J.J.,Yeh, J.I.,Smithgall, T.E. (deposition date: 2014-07-25, release date: 2014-08-20, Last modification date: 2023-09-27)

Primary citation

Alvarado, J.J.,Tarafdar, S.,Yeh, J.I.,Smithgall, T.E.
Interaction with the Src Homology (SH3-SH2) Region of the Src-family Kinase Hck Structures the HIV-1 Nef Dimer for Kinase Activation and Effector Recruitment.
J.Biol.Chem., 289:28539-28553, 2014

PubMed Abstract: HIV-1 Nef supports high titer viral replication in vivo and is essential for AIDS progression. Nef function depends on interactions with multiple host cell effectors, including Hck and other Src-family kinases. Here we describe the x-ray crystal structure of Nef in complex with the Hck SH3-SH2 regulatory region to a resolution of 1.86 Å. The complex crystallized as a dimer of complexes, with the conserved Nef PXXPXR motif engaging the Hck SH3 domain. A new intercomplex contact was found between SH3 Glu-93, and Nef Arg-105. Mutagenesis of Hck SH3 Glu-93 interfered with Nef·Hck complex formation and kinase activation in cells. The Hck SH2 domains impinge on the N-terminal region of Nef to stabilize a dimer conformation that exposes Asp-123, a residue critical for Nef function. Our results suggest that in addition to serving as a kinase effector for Nef, Hck binding may reorganize the Nef dimer for functional interaction with other signaling partners.

PubMed: 25122770
DOI: 10.1074/jbc.M114.600031

Experimental method

X-RAY DIFFRACTION (1.86 Å)