PMID- 29629773
OWN - NLM
STAT- MEDLINE
DCOM- 20190304
LR  - 20190304
IS  - 1520-5207 (Electronic)
IS  - 1520-5207 (Linking)
VI  - 122
IP  - 17
DP  - 2018 May 3
TI  - Conformational Plasticity in Tyrosine Kinase Inhibitor-Kinase Interactions 
      Revealed with Fluorescence Spectroscopy and Theoretical Calculations.
PG  - 4667-4679
LID - 10.1021/acs.jpcb.8b01530 [doi]
AB  - To understand drug-protein dynamics, it is necessary to account for drug 
      molecular flexibility and binding site plasticity. Herein, we exploit 
      fluorescence from a tyrosine kinase inhibitor, AG1478, as a reporter of its 
      conformation and binding site environment when complexed with its cognate kinase. 
      Water-soluble kinases, aminoglycoside phosphotransferase APH(3')-Ia and 
      mitogen-activated protein kinase 14 (MAPK14), were chosen for this study. On the 
      basis of our prior work, the AG1478 conformation (planar or twisted) was inferred 
      from the fluorescence excitation spectrum and the polarity of the AG1478-binding 
      site was deduced from the fluorescence emission spectrum, while red-edge 
      excitation shift (REES) probed the heterogeneity of the binding site (protein 
      conformation and hydration) distributions in the protein conformational ensemble. 
      In the AG1478-APH(3')-Ia complex, both twisted (or partially twisted) and planar 
      AG1478 conformations were evidenced from emission wavelength-dependent excitation 
      spectra. The binding site environment provided by APH(3')-Ia was moderately polar 
      (lambda(max) = 480 nm) with evidence for considerable heterogeneity (REES = 34 nm). In 
      contrast, in the AG1478-MAPK14 complex, AG1478 was in a predominantly planar 
      conformation with a lower degree of conformational heterogeneity. The binding 
      site environment provided by the MAPK14 protein was of relatively low polarity 
      (lambda(max) = 430 nm) with a smaller degree of heterogeneity (REES = 11 nm). The 
      results are compared with the available X-ray data and discussed in the context 
      of our current understanding of tyrosine kinase inhibitor conformation and 
      protein conformational ensembles.
FAU - Khattab, Muhammad
AU  - Khattab M
AUID- ORCID: 0000-0002-9086-8983
FAU - Wang, Feng
AU  - Wang F
AUID- ORCID: 0000-0002-6584-0516
FAU - Clayton, Andrew H A
AU  - Clayton AHA
AUID- ORCID: 0000-0002-6182-3049
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180420
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Databases, Protein
MH  - *Models, Molecular
MH  - Molecular Conformation
MH  - Protein Binding
MH  - Protein Kinase Inhibitors/*chemistry/*pharmacology
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Spectrometry, Fluorescence
EDAT- 2018/04/10 06:00
MHDA- 2019/03/05 06:00
CRDT- 2018/04/10 06:00
PHST- 2018/04/10 06:00 [pubmed]
PHST- 2019/03/05 06:00 [medline]
PHST- 2018/04/10 06:00 [entrez]
AID - 10.1021/acs.jpcb.8b01530 [doi]
PST - ppublish
SO  - J Phys Chem B. 2018 May 3;122(17):4667-4679. doi: 10.1021/acs.jpcb.8b01530. Epub 
      2018 Apr 20.