4OYD

Crystal structure of a computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein

Summary for 4OYD

• Entry DOI: 10.2210/pdb4oyd/pdb
• Descriptor: Apoptosis regulator BHRF1, Computationally designed Inhibitor, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, apoptosis, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Epstein-Barr virus (HHV-4); More
• Cellular location: Host membrane ; Single-pass membrane protein : P0C6Z1
• Total number of polymer chains: 4
• Total formula weight: 64059.13

Authors

Shen, B.,Procko, E.,Baker, D.,Stoddard, B. (deposition date: 2014-02-11, release date: 2014-07-09, Last modification date: 2023-12-27)

Primary citation

Procko, E.,Berguig, G.Y.,Shen, B.W.,Song, Y.,Frayo, S.,Convertine, A.J.,Margineantu, D.,Booth, G.,Correia, B.E.,Cheng, Y.,Schief, W.R.,Hockenbery, D.M.,Press, O.W.,Stoddard, B.L.,Stayton, P.S.,Baker, D.
A computationally designed inhibitor of an epstein-barr viral bcl-2 protein induces apoptosis in infected cells.
Cell, 157:1644-1656, 2014

PubMed Abstract: Because apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus (EBV) gene BHRF1, a homolog of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High-specificity-designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates.

PubMed: 24949974
DOI: 10.1016/j.cell.2014.04.034

Experimental method

X-RAY DIFFRACTION (1.8 Å)