5XP5

C-Src in complex with ATP-Chf

Summary for 5XP5

• Entry DOI: 10.2210/pdb5xp5/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-[(S)-fluoranyl-[oxidanyl(phosphonooxy)phosphoryl]methyl]phosphinic acid, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Gallus gallus (Chicken)
• Total number of polymer chains: 2
• Total formula weight: 66548.30

Authors

Duan, Y.,Guo, M.,Dai, S.,Chen, L.,Chen, Y. (deposition date: 2017-06-01, release date: 2018-02-07, Last modification date: 2023-11-22)

Primary citation

Ni, F.,Kung, A.,Duan, Y.,Shah, V.,Amador, C.D.,Guo, M.,Fan, X.,Chen, L.,Chen, Y.,McKenna, C.E.,Zhang, C.
Remarkably Stereospecific Utilization of ATP alpha , beta-Halomethylene Analogues by Protein Kinases.
J. Am. Chem. Soc., 139:7701-7704, 2017

PubMed Abstract: ATP analogues containing a CXY group in place of the α,β-bridging oxygen atom are powerful chemical probes for studying ATP-dependent enzymes. A limitation of such probes has been that conventional synthetic methods generate a mixture of diastereomers when the bridging carbon substitution is nonequivalent (X ≠ Y). We report here a novel method based on derivatization of a bisphosphonate precursor with a d-phenylglycine chiral auxiliary that enables preparation of the individual diastereomers of α,β-CHF-ATP and α,β-CHCl-ATP, which differ only in the configuration at the CHX carbon. When tested on a dozen divergent protein kinases, these individual diastereomers exhibit remarkable diastereospecificity (up to over 1000-fold) in utilization by the enzymes. This high selectivity can be exploited in an enzymatic approach to obtain the otherwise inaccessible diastereomers of α,β-CHBr-ATP. The crystal structure of a tyrosine kinase Src bound to α,β-CHX-ADP establishes the absolute configuration of the CHX carbon and helps clarify the origin of the remarkable diastereospecificity observed. We further synthesized the individual diastereomers of α,β-CHF-γ-thiol-ATP and demonstrated their utility in labeling a wide spectrum of kinase substrates. The novel ATP substrate analogues afforded by these two complementary strategies should have broad application in the study of the structure and function of ATP-dependent enzymes.

PubMed: 28535041
DOI: 10.1021/jacs.7b03266

Experimental method

X-RAY DIFFRACTION (2.101 Å)