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Title: High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site

Abstract

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.

Authors:
ORCiD logo [1];  [2];  [3];  [4];  [5];  [4]
  1. Univ. of Arizona, Tucson, AZ (United States). College of Pharmacy; Univ. of Arizona, Phoenix, AZ (United States). College of Medicine
  2. Shamrock Structures, LLC, Woodridge, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Neuro Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY (United States)
  4. Univ. of Arizona, Tucson, AZ (United States). College of Pharmacy
  5. Shamrock Structures, LLC, Woodridge, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1545850
Grant/Contract Number:  
[085P1000817]
Resource Type:
Accepted Manuscript
Journal Name:
BMC Molecular and Cell Biology
Additional Journal Information:
[ Journal Volume: 20; Journal Issue: 1]; Journal ID: ISSN 2661-8850
Country of Publication:
United States
Language:
ENGLISH
Subject:
Focal adhesion kinase; FERM domain; Drug discovery

Citation Formats

Marlowe, Timothy, Dementiev, Alexey, Figel, Sheila, Rivera, Andrew, Flavin, Michael, and Cance, William. High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site. United States: N. p., 2019. Web. doi:10.1186/s12860-019-0193-4.
Marlowe, Timothy, Dementiev, Alexey, Figel, Sheila, Rivera, Andrew, Flavin, Michael, & Cance, William. High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site. United States. doi:10.1186/s12860-019-0193-4.
Marlowe, Timothy, Dementiev, Alexey, Figel, Sheila, Rivera, Andrew, Flavin, Michael, and Cance, William. Mon . "High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site". United States. doi:10.1186/s12860-019-0193-4. https://www.osti.gov/servlets/purl/1545850.
@article{osti_1545850,
title = {High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site},
author = {Marlowe, Timothy and Dementiev, Alexey and Figel, Sheila and Rivera, Andrew and Flavin, Michael and Cance, William},
abstractNote = {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.},
doi = {10.1186/s12860-019-0193-4},
journal = {BMC Molecular and Cell Biology},
number = [1],
volume = [20],
place = {United States},
year = {2019},
month = {5}
}

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