Dynamics of human protein kinase Aurora A linked to drug selectivity

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Abstract

Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.

Data availability

Diffraction data have been deposited in PDB under the accession codes 6CPE, 6CPF, 6CPG.

The following data sets were generated

1. Otten R
2. Kutter S
3. Buosi V
4. Padua RAP
5. Kern D
(2018) Structure of apo, dephosphorylated Aurora A (122-403) in an active conformation
Publicly available at RCSB Protein Data Bank (accession no: 6CPE).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=6CPE
1. Otten R
2. Zorba A
3. Padua RAP
4. Kern D
(2018) Structure of dephosphorylated Aurora A (122-403) bound to AMPPCP in an active conformation
Publicly available at RCSB Protein Data Bank (accession no: 6CPF).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=6CPF
1. Otten R
2. Kutter S
3. Zorba A
4. Padua RAP
5. Kern D
(2018) Structure of dephosphorylated Aurora A (122-403) in complex with inhibiting monobody and AT9283 in an inactive conformation
Publicly available at RCSB Protein Data Bank (accession no: 6CPG).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=6CPG

The following previously published data sets were used

1. Zorba A
2. Kutter S
3. Cho Y-J
4. Kern D
(2014) Structure of dephosphorylated Aurora A (122-403) bound to AMPPCP
Publicly available at RCSB Protein Data Bank (accession no: 4C3R).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=4C3R
1. Cheetham GMT
2. Knegtel RMA
3. Coll JT
4. Renwick SB
5. Swenson L
6. Weber P
7. Lippke JA
8. Austen DA
(2003) CRYSTAL STRUCTURE OF AURORA-2, AN ONCOGENIC SERINE-THREONINE KINASE
Publicly available at RCSB Protein Data Bank (accession no: 1MUO).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=1MUO
1. Bayliss R
2. Conti E
(2003) Structure of Human Aurora-A 122-403 phosphorylated on Thr287, Thr288
Publicly available at RCSB Protein Data Bank (accession no: 1OL7).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=1OL7
1. Howard S
2. Berdini V
3. Boulstridge JA
4. Carr MG
5. Cross DM
6. Curry J
7. Devine LA
8. Early TR
9. Fazal L
10. Gill AL
11. Heathcote M
12. Maman S
13. Matthews JE
14. McMenamin RL
15. Navarro EF
16. O'Brien MA
17. O'Reilly M
18. Rees DC
19. Reule M
20. Tisi D
21. Williams G
22. Vinkovic M
23. Wyatt PG
(2009) Structure determination of Aurora Kinase in complex with inhibitor
Publicly available at RCSB Protein Data Bank (accession no: 2W1G).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=2W1G
1. Cameron AD
2. Izzo G
3. Storici P
4. Rusconi L
5. Fancelli D
6. Varasi M
7. Berta D
8. Bindi S
9. Forte B
10. Severino D
11. Tonani R
12. Vianello P
(2006) Structure of Aurora-2 in complex with PHA-739358
Publicly available at RCSB Protein Data Bank (accession no: 2J50).

https://www.rcsb.org/pdb/search/structidSearch.do?structureId=2J50

Article and author information

Author details

Warintra Pitsawong

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5438-1783
Vanessa Buosi

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.
Renee Otten

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7342-6131
Roman V Agafonov

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.
Adelajda Zorba

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4452-8419
Nadja Kern

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.
Steffen Kutter

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.
Gunther Kern

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.
Ricardo AP Pádua

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

Competing interests
The authors declare that no competing interests exist.
Xavier Meniche

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Dorothee Kern

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

For correspondence
dkern@brandeis.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7631-8328

Funding

Howard Hughes Medical Institute

Dorothee Kern

National Institutes of Health (GM100966-01)

Dorothee Kern

U.S. Department of Energy (DE-FG02-05ER15699)

Dorothee Kern

Damon Runyon Cancer Research Foundation (DRG-2114-12)

Renee Otten

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.