9RZZ

PYCR1 in complex with pyrrolidine-1-sulfonic acid.

This is a non-PDB format compatible entry.

Summary for 9RZZ

• Entry DOI: 10.2210/pdb9rzz/pdb
• Descriptor: Isoform 3 of Pyrroline-5-carboxylate reductase 1, mitochondrial, 1,2-ETHANEDIOL, pyrrolidine-1-sulfonic acid, ... (4 entities in total)
• Functional Keywords: delta-1-pyrroline-5-carboxylate reductase, pycr1, cancer, crystallographic fragment screening (xfs), molecular docking, inhibitors, proline metabolism, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 181183.36

Authors

Ragin-Oh, W.,Ruszkowski, M.,Czerwonka, D. (deposition date: 2025-07-16, release date: 2025-10-15)

Primary citation

Ragin-Oh, W.,Czerwonka, D.,Tran, L.H.,Forlani, G.,Ruszkowski, M.
Crystallographic fragment screening reveals new starting points for PYCR1 inhibitor design.
Bioorg.Chem., 165:109024-109024, 2025

PubMed Abstract: Pyrroline-5-carboxylate (P5C) reductase catalyzes the final step in proline biosynthesis. Human P5C reductase isoform 1 (PYCR1) has emerged as a key metabolic enzyme supporting cancer progression through its roles in redox homeostasis, collagen production, and the proline-P5C cycle. Despite its relevance as a therapeutic target, structural and chemical efforts to inhibit PYCR1 remain limited and have largely focused on proline analogs. Here, we report the first crystallographic fragment screening (XFS) campaign against PYCR1, employing a chemically diverse library of 96 compounds. We solved twelve co-crystal structures, featuring ligands occupying the P5C and NADH binding pockets, including dual-site ligands that span both regions. Among the newly identified moieties, sulfonamide and sulfamate groups emerged as notable isosteric replacements for the carboxylate group in the PYCR1 active site. Aromatic substituents in several compounds revealed a cryptic subpocket near the nicotinamide-binding site. Interestingly, halogen-substituted aromatic rings, often present in known PYCR1 inhibitors, exhibited distinct binding orientations, reflecting the flexibility and diversity of interactions in the binding subpockets. High-resolution structures revealed ligand-induced conformational changes in PYCR1, some involving significant rearrangements. Molecular dynamics simulations indicated that these conformations are accessible in the ligand-free enzyme, underscoring the intrinsic plasticity of PYCR1's active site.

PubMed: 41016381
DOI: 10.1016/j.bioorg.2025.109024

Experimental method

X-RAY DIFFRACTION (1.7 Å)