High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site.
Animals
Avian Proteins
/ chemistry
Binding Sites
Computer Simulation
Crystallization
Crystallography, X-Ray
Cytoskeletal Proteins
/ chemistry
Dimerization
Drug Discovery
/ methods
FERM Domains
Focal Adhesion Protein-Tyrosine Kinases
/ antagonists & inhibitors
Membrane Proteins
/ chemistry
Microfilament Proteins
/ chemistry
Phosphorylation
Protein Binding
Protein Structure, Secondary
Proto-Oncogene Proteins pp60(c-src)
/ chemistry
Tyrosine
/ chemistry
src Homology Domains
Drug discovery
FERM domain
Focal adhesion kinase
Journal
BMC molecular and cell biology
ISSN: 2661-8850
Titre abrégé: BMC Mol Cell Biol
Pays: England
ID NLM: 101741148
Informations de publication
Date de publication:
20 05 2019
20 05 2019
Historique:
received:
20
03
2019
accepted:
02
05
2019
entrez:
22
5
2019
pubmed:
22
5
2019
medline:
11
3
2020
Statut:
epublish
Résumé
Focal Adhesion Kinase (FAK) is a major cancer drug target that is involved in numerous aspects of tumor progression and survival. While multiple research groups have developed ATP-competitive small molecule inhibitors that target the kinase enzyme, recent attention has been focused on the FAK FERM (Band 4.1, Ezrin, Radixin, Moesin) domain that contains key residue Y397 and contributes to many protein-protein interactions. Previous x-ray crystal structures of the FAK FERM domain gave conflicting results on the structure of the Y397 region and therefore the overall druggability. Here, we report the identification of a higher resolution crystal structure of the avian FAK FERM domain that shows conformational differences in Y397 and surrounding residues in the F1 lobe. In addition, we resolve the residues of the Src SH3 binding site, an area of the FERM domain that has previously shown limited electron density. These crystallographic data suggest that the Y397 region is highly dynamic and question the druggability of a putative pocket on the F1 lobe. In addition, new electron density data around the Src SH3 binding site provide structural insight on the FAK-Src activation cascade through a putative auto-inhibitory conformation.
Sections du résumé
BACKGROUND
Focal Adhesion Kinase (FAK) is a major cancer drug target that is involved in numerous aspects of tumor progression and survival. While multiple research groups have developed ATP-competitive small molecule inhibitors that target the kinase enzyme, recent attention has been focused on the FAK FERM (Band 4.1, Ezrin, Radixin, Moesin) domain that contains key residue Y397 and contributes to many protein-protein interactions. Previous x-ray crystal structures of the FAK FERM domain gave conflicting results on the structure of the Y397 region and therefore the overall druggability.
RESULTS
Here, we report the identification of a higher resolution crystal structure of the avian FAK FERM domain that shows conformational differences in Y397 and surrounding residues in the F1 lobe. In addition, we resolve the residues of the Src SH3 binding site, an area of the FERM domain that has previously shown limited electron density.
CONCLUSIONS
These crystallographic data suggest that the Y397 region is highly dynamic and question the druggability of a putative pocket on the F1 lobe. In addition, new electron density data around the Src SH3 binding site provide structural insight on the FAK-Src activation cascade through a putative auto-inhibitory conformation.
Identifiants
pubmed: 31109284
doi: 10.1186/s12860-019-0193-4
pii: 10.1186/s12860-019-0193-4
pmc: PMC6528292
doi:
Substances chimiques
Avian Proteins
0
Cytoskeletal Proteins
0
Membrane Proteins
0
Microfilament Proteins
0
ezrin
0
moesin
144131-77-1
radixin
144517-21-5
Tyrosine
42HK56048U
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
Proto-Oncogene Proteins pp60(c-src)
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
10Subventions
Organisme : NCI NIH HHS
ID : R01 CA065910
Pays : United States
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