6G34

Crystal structure of haspin in complex with 5-iodotubercidin

Summary for 6G34

• Entry DOI: 10.2210/pdb6g34/pdb
• Descriptor: Serine/threonine-protein kinase haspin, (2R,3R,4S,5R)-2-(4-AMINO-5-IODO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL, IODIDE ION, ... (6 entities in total)
• Functional Keywords: kinase, inhibitors, slow off-rate, kinetics, halogen, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 41563.81

Authors

Heroven, C.,Chaikuad, A.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-03-24, release date: 2018-04-18, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.76 Å)