2VUW

Structure of human haspin kinase domain

2VUW の概要

• エントリーDOI: 10.2210/pdb2vuw/pdb
• 分子名称: SERINE/THREONINE-PROTEIN KINASE HASPIN, IODIDE ION, (2R,3R,4S,5R)-2-(4-AMINO-5-IODO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL, ... (7 entities in total)
• 機能のキーワード: cell cycle, transferase, casp8, nucleotide binding
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus : Q8TF76
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39389.05

構造登録者

Eswaran, J.,Murray, J.W.,Filippakopoulos, P.,Soundararajan, M.,Pike, A.C.W.,von Delft, F.,Picaud, S.,Keates, T.,King, O.,Wickstroem, M.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Fedorov, O.,Burgess-Brown, N.,Bray, J.,Knapp, S. (登録日: 2008-05-30, 公開日: 2008-09-16, 最終更新日: 2024-11-06)

主引用文献

Eswaran, J.,Patnaik, D.,Filippakopoulos, P.,Wang, F.,Stein, R.L.,Murray, J.W.,Higgins, J.M.G.,Knapp, S.
Structure and Functional Characterization of the Atypical Human Kinase Haspin.
Proc.Natl.Acad.Sci.USA, 106:20198-, 2009

PubMed Abstract: The protein kinase haspin/Gsg2 plays an important role in mitosis, where it specifically phosphorylates Thr-3 in histone H3 (H3T3). Its protein sequence is only weakly homologous to other protein kinases and lacks the highly conserved motifs normally required for kinase activity. Here we report structures of human haspin in complex with ATP and the inhibitor iodotubercidin. These structures reveal a constitutively active kinase conformation, stabilized by haspin-specific inserts. Haspin also has a highly atypical activation segment well adapted for specific recognition of the basic histone tail. Despite the lack of a DFG motif, ATP binding to haspin is similar to that in classical kinases; however, the ATP gamma-phosphate forms hydrogen bonds with the conserved catalytic loop residues Asp-649 and His-651, and a His651Ala haspin mutant is inactive, suggesting a direct role for the catalytic loop in ATP recognition. Enzyme kinetic data show that haspin phosphorylates substrate peptides through a rapid equilibrium random mechanism. A detailed analysis of histone modifications in the neighborhood of H3T3 reveals that increasing methylation at Lys-4 (H3K4) strongly decreases substrate recognition, suggesting a key role of H3K4 methylation in the regulation of haspin activity.

PubMed: 19918057
DOI: 10.1073/PNAS.0901989106

実験手法

X-RAY DIFFRACTION (1.8 Å)