7D7S

HIV-1 SF2 Nef in complex with the Fyn SH3 R96I mutant

7D7S の概要

• エントリーDOI: 10.2210/pdb7d7s/pdb
• 関連するPDBエントリー: 3H0F 3H0H 3H0I 4d8d 6IPY 6IPZ
• 分子名称: Protein Nef, Tyrosine-protein kinase Fyn (2 entities in total)
• 機能のキーワード: complex, mutant, kinase, sh3, viral protein
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2) (HIV-1); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 67681.65

構造登録者

Aldehaiman, A.,Shahul Hamed, U.F.,Arold, S.T. (登録日: 2020-10-05, 公開日: 2020-11-18, 最終更新日: 2023-11-29)

主引用文献

Aldehaiman, A.,Momin, A.A.,Restouin, A.,Wang, L.,Shi, X.,Aljedani, S.,Opi, S.,Lugari, A.,Shahul Hameed, U.F.,Ponchon, L.,Morelli, X.,Huang, M.,Dumas, C.,Collette, Y.,Arold, S.T.
Synergy and allostery in ligand binding by HIV-1 Nef.
Biochem.J., 478:1525-1545, 2021

PubMed Abstract: The Nef protein of human and simian immunodeficiency viruses boosts viral pathogenicity through its interactions with host cell proteins. By combining the polyvalency of its large unstructured regions with the binding selectivity and strength of its folded core domain, Nef can associate with many different host cell proteins, thereby disrupting their functions. For example, the combination of a linear proline-rich motif and hydrophobic core domain surface allows Nef to bind tightly and specifically to SH3 domains of Src family kinases. We investigated whether the interplay between Nef's flexible regions and its core domain could allosterically influence ligand selection. We found that the flexible regions can associate with the core domain in different ways, producing distinct conformational states that alter the way in which Nef selects for SH3 domains and exposes some of its binding motifs. The ensuing crosstalk between ligands might promote functionally coherent Nef-bound protein ensembles by synergizing certain subsets of ligands while excluding others. We also combined proteomic and bioinformatics analyses to identify human proteins that select SH3 domains in the same way as Nef. We found that only 3% of clones from a whole-human fetal library displayed Nef-like SH3 selectivity. However, in most cases, this selectivity appears to be achieved by a canonical linear interaction rather than by a Nef-like 'tertiary' interaction. Our analysis supports the contention that Nef's mode of hijacking SH3 domains is a virus-specific adaptation with no or very few cellular counterparts. Thus, the Nef tertiary binding surface is a promising virus-specific drug target.

PubMed: 33787846
DOI: 10.1042/BCJ20201002

実験手法

X-RAY DIFFRACTION (3.32 Å)