5HTB

Crystal structure of haspin (GSG2) in complex with bisubstrate inhibitor ARC-3353

Summary for 5HTB

• Entry DOI: 10.2210/pdb5htb/pdb
• Descriptor: Serine/threonine-protein kinase haspin, (2R,3S,4R,5R,6R)-6-((1R,2R,3S,4R,6S)-4,6-DIAMINO-2,3-DIHYDROXYCYCLOHEXYLOXY)-5-AMINO-2-(AMINOMETHYL)-TETRAHYDRO-2H-PYRAN-3,4-DIOL, (4R)-2-METHYLPENTANE-2,4-DIOL, ... (8 entities in total)
• Functional Keywords: transferase, kinase, inhibitor, allosteric, structural genomics consortium (sgc), transferase-transferase inhibitor complex, bisubstrate inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q8TF76
• Total number of polymer chains: 2
• Total formula weight: 42360.40

Authors

Chaikuad, A.,Heroven, C.,Lavogina, D.,Kestav, K.,Uri, A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2016-01-26, release date: 2016-05-11, Last modification date: 2024-12-04)

Primary citation

Lavogina, D.,Kestav, K.,Chaikuad, A.,Heroven, C.,Knapp, S.,Uri, A.
Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors.
Acta Crystallogr.,Sect.F, 72:339-345, 2016

PubMed Abstract: Haspin is a mitotic protein kinase that is responsible for the phosphorylation of Thr3 of histone H3, thereby creating a recognition motif for docking of the chromosomal passenger complex that is crucial for the progression of cell division. Here, two high-resolution models of haspin with previously reported inhibitors consisting of an ATP analogue and a histone H3(1-7) peptide analogue are presented. The structures of the complexes confirm the bisubstrate character of the inhibitors by revealing the signature binding modes of the moieties targeting the ATP-binding site and the protein substrate-binding site of the kinase. This is the first structural model of a bisubstrate inhibitor targeting haspin. The presented structural data represent a model for the future development of more specific haspin inhibitors.

PubMed: 27139824
DOI: 10.1107/S2053230X16004611

Experimental method

X-RAY DIFFRACTION (1.7 Å)