Synergy and allostery in ligand binding by HIV-1 Nef

Abdullah M Aldehaiman, Afaque Ahmad Imtiyaz Momin, Audrey Restouin, Luyao Wang, Xiaoli Shi, Safia Salim Eid Aljedani, Sandrine Opi, Adrien Lugari, Umar F Shahul Hameed, Luc Ponchon, Xavier Morelli, Mingdong Huang, Christian Dumas, Yves Collette, Stefan T. Arold

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.
Original languageEnglish (US)
JournalBiochemical Journal
StatePublished - Mar 31 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-04-02
Acknowledged KAUST grant number(s): FCC/1/1976-25
Acknowledgements: We acknowledge SOLEIL for the provision of synchrotron radiation facilities. We also thank L. Chavas, P. Legrand, S. Sirigu, and P. Montaville for their assistance with beamline PROXIMA 1 and G. Fox, M. Savko, and B. Shepard with PROXIMA 2A. We also thank M-P. Struband and M-T. Augé-Sénégas for the initial cloning of some of the FynR96I and FynR96W mutants. We thank M. Geyer for providing the expression construct of Nef SF2. We acknowledge the staff at ESRF beamline BM30, Grenoble, France, for their assistance with crystallographic data collection. We also thank the KAUST Supercomputing Laboratory for their assistance with computational resources for molecular dynamics simulations using the IBEX cluster.

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


Dive into the research topics of 'Synergy and allostery in ligand binding by HIV-1 Nef'. Together they form a unique fingerprint.

Cite this