Bromine sad partially resolves multiple binding modes for pka inhibitor h-89
Structure:
Camp-dependent protein kinase catalytic subunit alpha. Chain: a. Synonym: pka c-alpha. Engineered: yes. Camp-dependent protein kinase inhibitor alpha. Chain: b. Fragment: unp resodues 6-25. Synonym: pki-alpha, camp-dependent protein kinase inhibitor, muscle/brain isoform.
Source:
Homo sapiens. Human. Organism_taxid: 9606. Gene: pkaca, prkaca. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide fragment of pki was synthesized by gl biochem (shanghai) ltd.
Resolution:
1.95Å
R-factor:
0.192
R-free:
0.234
Authors:
A.Pflug,K.A.Johnson,R.A.Engh
Key ref:
A.Pflug
et al.
(2012).
Anomalous dispersion analysis of inhibitor flexibility: a case study of the kinase inhibitor H-89.
Acta Crystallogr Sect F Struct Biol Cryst Commun,
68,
873-877.
PubMed id: 22869112
Anomalous dispersion analysis of inhibitor flexibility: a case study of the kinase inhibitor H-89.
A.Pflug,
K.A.Johnson,
R.A.Engh.
ABSTRACT
With its ability to show the interactions between drug-target proteins and
small-molecule ligands, X-ray crystallography is an essential tool in
drug-discovery programmes. However, its usefulness can be limited by
crystallization artifacts or by the data resolution, and in particular when
assumptions of unimodal binding (and isotropic motion) do not apply.
Discrepancies between the modelled crystal structure and the physiological range
of structures generally prevent quantitative estimation of binding energies.
Improved crystal structure resolution will often not aid energy estimation
because the conditions which provide the highest rigidity and resolution are not
likely to reflect physiological conditions. Instead, strategies must be employed
to measure and model flexibility and multiple binding modes to supplement
crystallographic information. One useful tool is the use of anomalous dispersion
for small molecules that contain suitable atoms. Here, an analysis of the
binding of the kinase inhibitor H-89 to protein kinase A (PKA) is presented.
H-89 contains a bromobenzene moiety that apparently binds with multiple
conformations in the kinase ATP pocket. Using anomalous dispersion methods, it
was possible to resolve these conformations into two distinct binding geometries.
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