PDBsum entry 3reb

Protein binding

PDB id: 3reb

Contents

Protein chains

106 a.a.

59 a.a.

114 a.a.

60 a.a.

PDB id:

3reb

Name:

Protein binding

Title:

HIV-1 nef protein in complex with engineered hck-sh3 domain

Structure:

Protein nef. Chain: a, c. Synonym: 3'orf, negative factor, f-protein, c-terminal core protein. Engineered: yes. Mutation: yes. Tyrosine-protein kinase hck. Chain: b, d. Synonym: hemopoietic cell kinase, p59-hck/p60-hck. Engineered: yes.

Source:

HIV-1 m:b_arv2/sf2. HIV-1. Organism_taxid: 11685. Strain: sf2. Gene: HIV-1 nef, nef. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human.

Resolution:

3.45Å R-factor: 0.217 R-free: 0.243

Authors:

A.Schulte,W.Blankenfeldt,M.Geyer

Key ref:

S.Breuer et al. (2011). Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef. PLoS One, 6, e20033. PubMed id: 21625496

Date:

04-Apr-11 Release date: 01-Jun-11

Protein chain

P03407  (NEF_HV1A2) -  Protein Nef from Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2)

Seq: 210 a.a.

Struc: 106 a.a.

Protein chain

P08631  (HCK_HUMAN) -  Tyrosine-protein kinase HCK from Homo sapiens

Seq: 526 a.a.

Struc: 59 a.a.*

Protein chain

P03407  (NEF_HV1A2) -  Protein Nef from Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2)

Seq: 210 a.a.

Struc: 114 a.a.

Protein chain

P08631  (HCK_HUMAN) -  Tyrosine-protein kinase HCK from Homo sapiens

Seq: 526 a.a.

Struc: 60 a.a.*

* PDB and UniProt seqs differ at 12 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, C: E.C.?
• Enzyme class 3: Chains B, D: 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

PLoS One 6:e20033 (2011)

PubMed id: 21625496

Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.

S.Breuer, S.I.Schievink, A.Schulte, W.Blankenfeldt, O.T.Fackler, M.Geyer.

ABSTRACT

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.