PDBsum entry 1avz

Complex (myristylation/transferase)

PDB id: 1avz

Contents

Protein chains

100 a.a. *

57 a.a. *

* Residue conservation analysis

PDB id:

1avz

Name:

Complex (myristylation/transferase)

Title:

V-1 nef protein in complex with wild type fyn sh3 domain

Structure:

Negative factor. Chain: a, b. Fragment: conserved core domain. Synonym: nef, f-protein. Engineered: yes. Mutation: yes. Fyn tyrosine kinase. Chain: c. Fragment: src-homology 3 domain.

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Variant: lai isolate. Cell_line: bl21. Gene: HIV-1 nef. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Homo sapiens. Human.

Biol. unit:

Trimer (from PQS)

Resolution:

3.00Å R-factor: 0.220 R-free: 0.270

Authors:

S.Arold,P.Franken,C.Dumas

Key ref:

S.Arold et al. (1997). The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling. Structure, 5, 1361-1372. PubMed id: 9351809 DOI: 10.1016/S0969-2126(97)00286-4

Date:

23-Sep-97 Release date: 25-Mar-98

Protein chains

P03406  (NEF_HV1BR) -  Protein Nef from Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)

Seq: 206 a.a.

Struc: 100 a.a.

Protein chain

P06241  (FYN_HUMAN) -  Tyrosine-protein kinase Fyn from Homo sapiens

Seq: 537 a.a.

Struc: 57 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, B: E.C.?
• Enzyme class 3: Chain C: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/S0969-2126(97)00286-4

Structure 5:1361-1372 (1997)

PubMed id: 9351809

The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling.

S.Arold, P.Franken, M.P.Strub, F.Hoh, S.Benichou, R.Benarous, C.Dumas.

ABSTRACT

BACKGROUND: Human immunodeficiency virus (HIV) Nef protein accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases. The structures of free Nef and Nef bound to Src homology region 3 (SH3) domain are important for the elucidation of how the affinity and specificity for the Src kinase family SH3 domains are achieved, and also for the development of potential drugs and vaccines against AIDS. RESULTS: We have determined the crystal structures of the conserved core of HIV-1 Nef protein alone and in complex with the wild-type SH3 domain of the p59fyn protein tyrosine kinase (Fyn), at 3.0 A resolution. Comparison of the bound and unbound Nef structures revealed that a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding, is partially disordered in the absence of the binding partner; this motif only fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. In addition, the structures show how an arginine residue (Arg77) of Nef interacts with Asp 100 of the so-called RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef as the isoleucine residue of a previously described Fyn SH3 (Arg96-->lle) mutant that binds to Nef with higher affinity than the wild type. CONCLUSIONS: The three-dimensional structures support evidence that the Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. The structures of bound and unbound Nef reveal that the multivalency of SH3 binding may be achieved by a ligand induced flexibility in the RT loop. The structures suggest possible targets for the design of inhibitors which specifically block Nef-SH3 interactions.

Selected figure(s)

Figure 7.
Figure 7. Superimposition of the crystal structures of Nef–SH3 complexes. Stereoview of the interface showing the environment of the Nef polyproline type II helix region (residues 71–77) and conserved residues. The two Nef isolates are superimposed: Nef HIV-1[LAI] isolate in green and Nef[T71R] HIV-1[NL43] isolate (Nef-D molecule in PDB entry 1EFN in red. The hydrogen bond between the Arg71 sidechain and Tyr137 of Fyn[R96I] is shown as a dotted white line. The SH3 domains are coloured in light purple and dark purple for Fyn[wt] and Fyn[R96I] (SH3-C molecule in PDB entry 1EFN), respectively. (Figure generated using the program O [69].)

The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 1361-1372) copyright 1997.

Figure was selected by an automated process.