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A molecular dynamics study of WPD-loop flexibility in PTP1B

Kamerlin, Shina Caroline Lynn LU orcid ; Rucker, Robert and Boresch, Stefan (2007) In Biochemical and Biophysical Research Communications 356(4). p.6-1011
Abstract

Protein tyrosine phosphatase 1B (PTP1B) is an important drug target for the treatment of type II diabetes and obesity. There are strong indications that a novel class of allosteric inhibitors act by preventing the closure of the WPD-loop [C. Wiesmann, K.J. Barr, J. Kung, J. Zhu, D.A. Erlanson, W. Shen, B.J. Fahr, M. Zhong, L. Taylor, M. Randall, R.S. McDowell, S.K. Hansen, Allosteric inhibition of protein tyrosine phosphatase 1B, Nat. Struc. Mol. Biol. 11 (2004) 730-737.], which is absolutely essential for the catalytic activity of PTP1B. In this work, we develop force field parameters for one of these inhibitors (BB3), and subsequently utilise standard and targeted molecular dynamics simulations to perform a study of WPD-loop mobility... (More)

Protein tyrosine phosphatase 1B (PTP1B) is an important drug target for the treatment of type II diabetes and obesity. There are strong indications that a novel class of allosteric inhibitors act by preventing the closure of the WPD-loop [C. Wiesmann, K.J. Barr, J. Kung, J. Zhu, D.A. Erlanson, W. Shen, B.J. Fahr, M. Zhong, L. Taylor, M. Randall, R.S. McDowell, S.K. Hansen, Allosteric inhibition of protein tyrosine phosphatase 1B, Nat. Struc. Mol. Biol. 11 (2004) 730-737.], which is absolutely essential for the catalytic activity of PTP1B. In this work, we develop force field parameters for one of these inhibitors (BB3), and subsequently utilise standard and targeted molecular dynamics simulations to perform a study of WPD-loop mobility in the presence of this inhibitor. We demonstrate that BB3 not only significantly reduces the flexibility of the WPD-loop compared to both the apo-enzyme or the closed conformation complexed with phosphotyrosine, but that this is accompanied by reduced flexibility in a related region, the S-loop, further emphasising the possibility of manipulating this region when designing novel inhibitors for PTP1B.

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author
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publishing date
type
Contribution to journal
publication status
published
keywords
Computer Simulation, Models, Chemical, Models, Molecular, Protein Conformation, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases/chemistry, Structure-Activity Relationship
in
Biochemical and Biophysical Research Communications
volume
356
issue
4
pages
6 pages
publisher
Elsevier
external identifiers
  • scopus:34047142165
  • pmid:17408595
ISSN
0006-291X
DOI
10.1016/j.bbrc.2007.03.093
language
English
LU publication?
no
id
5a6cdc05-a80c-438a-95ab-3135b5a0841c
date added to LUP
2025-01-11 22:19:20
date last changed
2025-01-23 03:22:07
@article{5a6cdc05-a80c-438a-95ab-3135b5a0841c,
  abstract     = {{<p>Protein tyrosine phosphatase 1B (PTP1B) is an important drug target for the treatment of type II diabetes and obesity. There are strong indications that a novel class of allosteric inhibitors act by preventing the closure of the WPD-loop [C. Wiesmann, K.J. Barr, J. Kung, J. Zhu, D.A. Erlanson, W. Shen, B.J. Fahr, M. Zhong, L. Taylor, M. Randall, R.S. McDowell, S.K. Hansen, Allosteric inhibition of protein tyrosine phosphatase 1B, Nat. Struc. Mol. Biol. 11 (2004) 730-737.], which is absolutely essential for the catalytic activity of PTP1B. In this work, we develop force field parameters for one of these inhibitors (BB3), and subsequently utilise standard and targeted molecular dynamics simulations to perform a study of WPD-loop mobility in the presence of this inhibitor. We demonstrate that BB3 not only significantly reduces the flexibility of the WPD-loop compared to both the apo-enzyme or the closed conformation complexed with phosphotyrosine, but that this is accompanied by reduced flexibility in a related region, the S-loop, further emphasising the possibility of manipulating this region when designing novel inhibitors for PTP1B.</p>}},
  author       = {{Kamerlin, Shina Caroline Lynn and Rucker, Robert and Boresch, Stefan}},
  issn         = {{0006-291X}},
  keywords     = {{Computer Simulation; Models, Chemical; Models, Molecular; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases/chemistry; Structure-Activity Relationship}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{4}},
  pages        = {{6--1011}},
  publisher    = {{Elsevier}},
  series       = {{Biochemical and Biophysical Research Communications}},
  title        = {{A molecular dynamics study of WPD-loop flexibility in PTP1B}},
  url          = {{http://dx.doi.org/10.1016/j.bbrc.2007.03.093}},
  doi          = {{10.1016/j.bbrc.2007.03.093}},
  volume       = {{356}},
  year         = {{2007}},
}