8TN6

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

8TN6 の概要

• エントリーDOI: 10.2210/pdb8tn6/pdb
• 分子名称: De novo designed protein, Rucaparib (3 entities in total)
• 機能のキーワード: drug binding, 4-helix bundle, de novo design, parpi, de novo protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 49581.93

構造登録者

Lu, L.,DeGrado, W.F. (登録日: 2023-08-01, 公開日: 2024-04-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.36 Å)