9J3P

Human Pigment Epithelium-Derived Factor with Zinc Ions Crystallized in P2(1)2(1)2(1) Space Group

Summary for 9J3P

• Entry DOI: 10.2210/pdb9j3p/pdb
• Descriptor: Pigment epithelium-derived factor, ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: metal-binding protein, signaling protein, neurotrophic factor, anti-tumorigenic factor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 223720.78

Authors

Belousov, A.S.,Chistyakov, D.V.,Baksheeva, V.E.,Bulgakov, T.K.,Bukhdruker, S.S.,Zamyatnin, A.A.,Zinchenko, D.V.,Tsvetkov, P.O.,Permyakov, S.E.,Zernii, E.Y.,Borshchevskiy, V.I. (deposition date: 2024-08-08, release date: 2025-06-18, Last modification date: 2025-10-15)

Primary citation

Chistyakov, D.V.,Belousov, A.S.,Shevelyova, M.P.,Iomdina, E.N.,Baksheeva, V.E.,Shebardina, N.G.,Moysenovich, A.M.,Bulgakov, T.K.,Petrov, S.Y.,Shishkin, M.L.,Tulush, S.S.,Tiulina, V.V.,Pogodina, E.I.,Gancharova, O.S.,Filippova, O.M.,Baldin, A.V.,Goriainov, S.V.,Nikolskaya, A.I.,Zalevsky, A.O.,Deviatkin, A.A.,Vologzhannikova, A.A.,Gorokhovets, N.V.,Litus, E.A.,Komarov, S.V.,Devred, F.,Sergeeva, M.G.,Mishin, A.V.,Bukhdruker, S.S.,Wu, L.,Araujo, E.A.,Zamyatnin Jr., A.A.,Senin, I.I.,Zinchenko, D.V.,Tsvetkov, P.O.,Borshchevskiy, V.I.,Permyakov, S.E.,Zernii, E.Y.
A role of pigment epithelium-derived factor in zinc-mediated mechanism of neurodegeneration in glaucoma.
Commun Biol, 8:965-965, 2025

PubMed Abstract: Glaucoma is a neurodegenerative condition involving optic nerve damage and retinal ganglion cells death. Animal studies suggested that the pathway linking these events can be mediated by mobile zinc secreted into the intraretinal space and exerting cytotoxic effects. Whether this mechanism is relevant for human glaucoma and what are the targets of extracellular zinc is unknown. We report that increased zinc content in the aqueous humor and retina is indeed a characteristic of glaucomatous neuropathy, and excess extracellular zinc may be recognized by the key retinal neurotrophic factor PEDF. Biophysical and X-ray crystallographic studies show that PEDF coordinates zinc ions in five types of intermolecular high-affinity sites, leading to a decrease in negative surface charge and reversible oligomerization of the protein, thereby masking the target recognition sites responsible for its neurotrophic and antiangiogenic activities and collagen binding. Notably, PEDF secretion is enhanced in both glaucoma and retinal cell models in response to zinc stress; however, zinc binding negatively affects axogenic, differentiative and prosurvival functions of PEDF by suppressing its ability to activate receptor PEDF-R/PNPLA2. We suggest that glaucomatous neurodegeneration is associated with direct inhibition of PEDF signaling by extracellular zinc, making their complex a promising target for neuroprotective therapy.

PubMed: 40596696
DOI: 10.1038/s42003-025-08370-8

Experimental method

X-RAY DIFFRACTION (2.1 Å)