Loop dynamics, allostery, and function in protein tyrosine phosphatases : insights from molecular simulations
Welsh, Colin L. and Kamerlin, Shina Caroline Lynn LU
(2026)
In Biochemical Society Transactions
54(1).
p.1-12
- Abstract
Enzymes are dynamic entities, and their conformational dynamics are intimately linked to their function and evolvability. In this context, protein tyrosine phosphatases (PTPs) are an excellent model system to probe the role of conformational dynamics in enzyme function and evolution. They are a genetically diverse family of enzymes, with a highly conserved catalytic domain, identical catalytic mechanisms, and turnover numbers that vary by orders of magnitude, with their activity being determined by the mobility of a catalytic loop that closes over the active site and places a key catalytic residue in place for efficient catalysis. From a biological perspective, PTPs are important regulators of a host of cellular processes, including... (More)
Enzymes are dynamic entities, and their conformational dynamics are intimately linked to their function and evolvability. In this context, protein tyrosine phosphatases (PTPs) are an excellent model system to probe the role of conformational dynamics in enzyme function and evolution. They are a genetically diverse family of enzymes, with a highly conserved catalytic domain, identical catalytic mechanisms, and turnover numbers that vary by orders of magnitude, with their activity being determined by the mobility of a catalytic loop that closes over the active site and places a key catalytic residue in place for efficient catalysis. From a biological perspective, PTPs are important regulators of a host of cellular processes, including cellular signaling, which has made them in particular important anticancer drug targets, among other diseases of interest. The high structural conservation of their active sites renders them therapeutically elusive, but there exist allosteric inhibitors that exploit the allosteric regulation of these enzymes to impede the motion of their catalytic WPD-loops, thus inactivating them. Conformational dynamics and allostery are problems that are ideal for computational investigation, and indeed, advances in computational methodologies have resulted in a range of exciting studies illuminating the molecular details of structure–function–dynamics–allostery links in these enzymes. This review provides both a brief history of computational work in this space, as well as discussing in detail recent advances, illustrating how molecular simulations have been successfully exploited to enhance our fundamental understanding of these biomedically important enzymes, and of the function and regulation of ‘loopy’ enzymes more broadly.
(Less)
- author
- Welsh, Colin L.
and Kamerlin, Shina Caroline Lynn
LU
- organization
- publishing date
- 2026
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Biochemical Society Transactions
- volume
- 54
- issue
- 1
- pages
- 12 pages
- publisher
- Portland Press
- external identifiers
-
- scopus:105028138317
- pmid:41562625
- ISSN
- 0300-5127
- DOI
- 10.1042/BST20250018
- language
- English
- LU publication?
- yes
- id
- d18de6c4-8879-4d90-97ea-ded0d9b431c2
- date added to LUP
- 2026-02-25 12:31:28
- date last changed
- 2026-03-11 13:59:34
@article{d18de6c4-8879-4d90-97ea-ded0d9b431c2,
abstract = {{<p>Enzymes are dynamic entities, and their conformational dynamics are intimately linked to their function and evolvability. In this context, protein tyrosine phosphatases (PTPs) are an excellent model system to probe the role of conformational dynamics in enzyme function and evolution. They are a genetically diverse family of enzymes, with a highly conserved catalytic domain, identical catalytic mechanisms, and turnover numbers that vary by orders of magnitude, with their activity being determined by the mobility of a catalytic loop that closes over the active site and places a key catalytic residue in place for efficient catalysis. From a biological perspective, PTPs are important regulators of a host of cellular processes, including cellular signaling, which has made them in particular important anticancer drug targets, among other diseases of interest. The high structural conservation of their active sites renders them therapeutically elusive, but there exist allosteric inhibitors that exploit the allosteric regulation of these enzymes to impede the motion of their catalytic WPD-loops, thus inactivating them. Conformational dynamics and allostery are problems that are ideal for computational investigation, and indeed, advances in computational methodologies have resulted in a range of exciting studies illuminating the molecular details of structure–function–dynamics–allostery links in these enzymes. This review provides both a brief history of computational work in this space, as well as discussing in detail recent advances, illustrating how molecular simulations have been successfully exploited to enhance our fundamental understanding of these biomedically important enzymes, and of the function and regulation of ‘loopy’ enzymes more broadly.</p>}},
author = {{Welsh, Colin L. and Kamerlin, Shina Caroline Lynn}},
issn = {{0300-5127}},
language = {{eng}},
number = {{1}},
pages = {{1--12}},
publisher = {{Portland Press}},
series = {{Biochemical Society Transactions}},
title = {{Loop dynamics, allostery, and function in protein tyrosine phosphatases : insights from molecular simulations}},
url = {{http://dx.doi.org/10.1042/BST20250018}},
doi = {{10.1042/BST20250018}},
volume = {{54}},
year = {{2026}},
}