5TZP

Crystal structure of FPV039:Bik BH3 complex

Summary for 5TZP

• Entry DOI: 10.2210/pdb5tzp/pdb
• Related: 5TZQ
• Descriptor: Bcl-2-like protein FPV039, Bik, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: bcl-2, apoptosis, fowlpox, poxvirus, bh3-only
• Biological source: Fowlpox virus (strain NVSL) (FPV); More
• Total number of polymer chains: 2
• Total formula weight: 21040.63

Authors

Anasir, M.I.,Kvansakul, M. (deposition date: 2016-11-22, release date: 2017-05-03, Last modification date: 2024-04-03)

Primary citation

Anasir, M.I.,Caria, S.,Skinner, M.A.,Kvansakul, M.
Structural basis of apoptosis inhibition by the fowlpox virus protein FPV039.
J. Biol. Chem., 292:9010-9021, 2017

PubMed Abstract: Programmed cell death or apoptosis of infected host cells is an important defense mechanism in response to viral infections. This process is regulated by proapoptotic and prosurvival members of the B-cell lymphoma 2 (Bcl-2) protein family. To counter premature death of a virus-infected cell, poxviruses use a range of different molecular strategies including the mimicry of prosurvival Bcl-2 proteins. One such viral prosurvival protein is the fowlpox virus protein FPV039, which is a potent apoptosis inhibitor, but the precise molecular mechanism by which FPV039 inhibits apoptosis is unknown. To understand how fowlpox virus inhibits apoptosis, we examined FPV039 using isothermal titration calorimetry, small-angle X-ray scattering, and X-ray crystallography. Here, we report that the fowlpox virus prosurvival protein FPV039 promiscuously binds to cellular proapoptotic Bcl-2 and engages all major proapoptotic Bcl-2 proteins. Unlike other identified viral Bcl-2 proteins to date, FPV039 engaged with cellular proapoptotic Bcl-2 with affinities comparable with those of Bcl-2's endogenous cellular counterparts. Structural studies revealed that FPV039 adopts the conserved Bcl-2 fold observed in cellular prosurvival Bcl-2 proteins and closely mimics the structure of the prosurvival Bcl-2 family protein Mcl-1. Our findings suggest that FPV039 is a pan-Bcl-2 protein inhibitor that can engage all host BH3-only proteins, as well as Bcl-2-associated X, apoptosis regulator (Bax) and Bcl-2 antagonist/killer (Bak) proteins to inhibit premature apoptosis of an infected host cell. This work therefore provides a mechanistic platform to better understand FPV039-mediated apoptosis inhibition.

PubMed: 28411240
DOI: 10.1074/jbc.M116.768879

Experimental method

X-RAY DIFFRACTION (1.35 Å)