8TND

De novo designed protein binds poly ADP ribose polymerase inhibitors (PARPi) - holo veliparib

Summary for 8TND

• Entry DOI: 10.2210/pdb8tnd/pdb
• Descriptor: De novo designed protein, (2R)-2-(7-carbamoyl-1H-benzimidazol-2-yl)-2-methylpyrrolidinium, SULFATE ION, ... (4 entities in total)
• Functional Keywords: drug binding, 4-helix bundle, de novo design, parpi, de novo protein, veliparib
• Biological source: synthetic construct
• Total number of polymer chains: 3
• Total formula weight: 49632.91

Authors

Lu, L.,DeGrado, W.F. (deposition date: 2023-08-01, release date: 2024-04-24)

Primary citation

Lu, L.,Gou, X.,Tan, S.K.,Mann, S.I.,Yang, H.,Zhong, X.,Gazgalis, D.,Valdiviezo, J.,Jo, H.,Wu, Y.,Diolaiti, M.E.,Ashworth, A.,Polizzi, N.F.,DeGrado, W.F.
De novo design of drug-binding proteins with predictable binding energy and specificity.
Science, 384:106-112, 2024

PubMed Abstract: The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free energy calculations performed directly on the designed models were in excellent agreement with the experimentally measured affinities. We conclude that de novo design of high-affinity small molecule-binding proteins with tuned interaction energies is feasible entirely from computation.

PubMed: 38574125
DOI: 10.1126/science.adl5364

Experimental method

X-RAY DIFFRACTION (1.29 Å)