---
_id: '3983'
abstract:
- lang: eng
text: Cdc25 phosphatases are key activators of the eukaryotic cell cycle and compelling
anticancer targets because their overexpression has been associated with numerous
cancers. However, drug discovery targeting these phosphatases has been hampered
by the lack of structural information about how Cdc25s interact with their native
protein substrates, the cyclin-dependent kinases. Herein, we predict a docked
orientation for Cdc25B with its Cdk2-pTpY-CycA protein substrate by a rigid-body
docking method and refine the docked models with full-scale molecular dynamics
simulations and minimization. We validate the stable ensemble structure experimentally
by a variety of in vitro and in vivo techniques. Specifically, we compare our
model with a crystal structure of the substrate-trapping mutant of Cdc25B. We
identify and validate in vivo a novel hot-spot residue on Cdc25B (Arg492) that
plays a central role in protein substrate recognition. We identify a hot-spot
residue on the Substrate Cdk2 (Asp206) and confirm its interaction with hot-spot
residues on Cdc25 using hot-spot swapping and double mutant cycles to derive interaction
energies. Our experimentally validated model is consistent with previous studies
of Cdk2 and its interaction partners and initiates the opportunity for drug discovery
of inhibitors that target the remote binding sites of this protein-protein interaction.
author:
- first_name: Jungsan
full_name: Sohn, Jungsan
last_name: Sohn
- first_name: Jerry
full_name: Parks, Jerry M
last_name: Parks
- first_name: Gregory
full_name: Buhrman, Gregory
last_name: Buhrman
- first_name: Paul
full_name: Brown, Paul
last_name: Brown
- first_name: Kolbrun
full_name: Kristjánsdóttir, Kolbrun
last_name: Kristjánsdóttir
- first_name: Alexias
full_name: Safi, Alexias
last_name: Safi
- first_name: Herbert
full_name: Herbert Edelsbrunner
id: 3FB178DA-F248-11E8-B48F-1D18A9856A87
last_name: Edelsbrunner
orcid: 0000-0002-9823-6833
- first_name: Weitao
full_name: Yang, Weitao T
last_name: Yang
- first_name: Johannes
full_name: Rudolph, Johannes
last_name: Rudolph
citation:
ama: Sohn J, Parks J, Buhrman G, et al. Experimental validation of the docking orientation
of Cdc25 with its Cdk2-CycA protein substrate. Biochemistry. 2005;44(50):16563-16573.
doi:10.1021/bi0516879
apa: Sohn, J., Parks, J., Buhrman, G., Brown, P., Kristjánsdóttir, K., Safi, A.,
… Rudolph, J. (2005). Experimental validation of the docking orientation of Cdc25
with its Cdk2-CycA protein substrate. Biochemistry. ACS. https://doi.org/10.1021/bi0516879
chicago: Sohn, Jungsan, Jerry Parks, Gregory Buhrman, Paul Brown, Kolbrun Kristjánsdóttir,
Alexias Safi, Herbert Edelsbrunner, Weitao Yang, and Johannes Rudolph. “Experimental
Validation of the Docking Orientation of Cdc25 with Its Cdk2-CycA Protein Substrate.”
Biochemistry. ACS, 2005. https://doi.org/10.1021/bi0516879.
ieee: J. Sohn et al., “Experimental validation of the docking orientation
of Cdc25 with its Cdk2-CycA protein substrate,” Biochemistry, vol. 44,
no. 50. ACS, pp. 16563–16573, 2005.
ista: Sohn J, Parks J, Buhrman G, Brown P, Kristjánsdóttir K, Safi A, Edelsbrunner
H, Yang W, Rudolph J. 2005. Experimental validation of the docking orientation
of Cdc25 with its Cdk2-CycA protein substrate. Biochemistry. 44(50), 16563–16573.
mla: Sohn, Jungsan, et al. “Experimental Validation of the Docking Orientation of
Cdc25 with Its Cdk2-CycA Protein Substrate.” Biochemistry, vol. 44, no.
50, ACS, 2005, pp. 16563–73, doi:10.1021/bi0516879.
short: J. Sohn, J. Parks, G. Buhrman, P. Brown, K. Kristjánsdóttir, A. Safi, H.
Edelsbrunner, W. Yang, J. Rudolph, Biochemistry 44 (2005) 16563–16573.
date_created: 2018-12-11T12:06:16Z
date_published: 2005-11-24T00:00:00Z
date_updated: 2021-01-12T07:53:39Z
day: '24'
doi: 10.1021/bi0516879
extern: 1
intvolume: ' 44'
issue: '50'
month: '11'
page: 16563 - 16573
publication: Biochemistry
publication_status: published
publisher: ACS
publist_id: '2144'
quality_controlled: 0
status: public
title: Experimental validation of the docking orientation of Cdc25 with its Cdk2-CycA
protein substrate
type: journal_article
volume: 44
year: '2005'
...