6G39

Crystal structure of haspin F605Y mutant in complex with 5-iodotubercidin

6G39 の概要

• エントリーDOI: 10.2210/pdb6g39/pdb
• 関連するPDBエントリー: 6g34
• 分子名称: Serine/threonine-protein kinase haspin, SODIUM ION, (2R,3R,4S,5R)-2-(4-AMINO-5-IODO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL, ... (6 entities in total)
• 機能のキーワード: kinase, inhibitors, slow off-rate, kinetics, halogen, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41505.88

構造登録者

Heroven, C.,Chaikuad, A.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2018-03-24, 公開日: 2018-04-18, 最終更新日: 2024-01-17)

主引用文献

Heroven, C.,Georgi, V.,Ganotra, G.K.,Brennan, P.,Wolfreys, F.,Wade, R.C.,Fernandez-Montalvan, A.E.,Chaikuad, A.,Knapp, S.
Halogen-Aromatic pi Interactions Modulate Inhibitor Residence Times.
Angew. Chem. Int. Ed. Engl., 57:7220-7224, 2018

PubMed Abstract: Prolonged drug residence times may result in longer-lasting drug efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active-state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen-aromatic π interactions in the haspin-inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding-energy calculations.

PubMed: 29601130
DOI: 10.1002/anie.201801666

実験手法

X-RAY DIFFRACTION (1.45 Å)