6FCM

Crystal structure of human PCNA

Summary for 6FCM

• Entry DOI: 10.2210/pdb6fcm/pdb
• Related: 1AXC
• Descriptor: Proliferating cell nuclear antigen (2 entities in total)
• Functional Keywords: proliferating cell nuclear antigen, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 93294.87

Authors

Housset, D.,Frachet, P. (deposition date: 2017-12-20, release date: 2019-01-30, Last modification date: 2024-10-16)

Primary citation

Ohayon, D.,De Chiara, A.,Dang, P.M.,Thieblemont, N.,Chatfield, S.,Marzaioli, V.,Burgener, S.S.,Mocek, J.,Candalh, C.,Pintard, C.,Tacnet-Delorme, P.,Renault, G.,Lagoutte, I.,Favier, M.,Walker, F.,Hurtado-Nedelec, M.,Desplancq, D.,Weiss, E.,Benarafa, C.,Housset, D.,Marie, J.C.,Frachet, P.,El-Benna, J.,Witko-Sarsat, V.
Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils.
J.Exp.Med., 216:2669-2687, 2019

PubMed Abstract: Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA interacted directly with the phox homology PX) domain of the p47phox. PCNA inhibition by competing peptides or by T2AA, a small-molecule PCNA inhibitor, decreased NADPH oxidase activation in vitro. Furthermore, T2AA provided a therapeutic benefit in mice during trinitro-benzene-sulfonic acid (TNBS)-induced colitis by decreasing oxidative stress, accelerating mucosal repair, and promoting the resolution of inflammation. Our data suggest that targeting PCNA in inflammatory neutrophils holds promise as a multifaceted antiinflammatory strategy.

PubMed: 31492810
DOI: 10.1084/jem.20180371

Experimental method

X-RAY DIFFRACTION (2.8 Å)