Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains.
computational biology
cryptic pockets
human
molecular biophysics
molecular dynamics
myosin
protein dynamics
specificity
structural biology
systems biology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
27 01 2023
27 01 2023
Historique:
received:
21
09
2022
accepted:
23
01
2023
pubmed:
28
1
2023
medline:
11
3
2023
entrez:
27
1
2023
Statut:
epublish
Résumé
The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin's binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R
Identifiants
pubmed: 36705568
doi: 10.7554/eLife.83602
pii: 83602
pmc: PMC9995120
doi:
pii:
Substances chimiques
Myosins
EC 3.6.4.1
Myosin Type II
EC 3.6.1.-
Protein Isoforms
0
Heterocyclic Compounds, 4 or More Rings
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : GM 20909
Pays : United States
Organisme : NIH HHS
ID : 1F30HL162431-01A1
Pays : United States
Organisme : NIH HHS
ID : R01 HL141086
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141086
Pays : United States
Organisme : NIH HHS
ID : NIGMS GM29090 to L.A.L
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30 HL162431
Pays : United States
Organisme : NIH HHS
ID : RF1AG067194
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM029090
Pays : United States
Organisme : NIH HHS
ID : R01 GM124007
Pays : United States
Informations de copyright
© 2023, Meller et al.
Déclaration de conflit d'intérêts
AM, JL, LS, BN, LL, CK, LG, LL, MG, GB No competing interests declared
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