Evidence map›Paper›PMID 34354111›Full record

ArticleScientific reports2021

Conformational dynamics of androgen receptors bound to agonists and antagonists.

Hyo Jin Gim, Jiyong Park, Michael E Jung, K N Houk

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed, 1 pooled it
3.2field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.

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  19. A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations.Acta crystallographica. Section F, Structural biology communications · 2023
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 1 institution in 1 country.

Hyo Jin Gim *Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095-1569, USA.
Jiyong Park *Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095-1569, USA.
Michael E JungDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095-1569, USA. jung@chem.ucla.edu.
K N HoukDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095-1569, USA. houk@chem.ucla.edu.
University of California, Los Angeles · US

Funding

Steroselectivity of Synthetically Valuable Enzyme CatalystsR01GM124480 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI HOUK, KENDALL N · 2018 to 2021
$1.1M
NIGMS NIH HHS R01 GM124480
6 · The paper itself

Abstract

The androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists. We have performed accelerated molecular dynamics (aMD) simulations of LBDs bound to a set of ligands including a natural substrate (dihydrotestosterone), an agonist (RU59063) and three antagonists (bicalutamide, enzalutamide and apalutamide) as well as in the absence of ligand (apo). We show that the binding of AR antagonists at the substrate binding pocket alter the dynamic fluctuations of H12, thereby disrupting the structural integrity of the agonistic conformation of AR. Two antagonists, enzalutamide and apalutamide, induce considerable structural changes to the agonist conformation of LBD, when bound close to H12 of AR LBD. When the antagonists bind to the pocket with different orientations having close contact with H11, no significant conformational changes were observed, suggesting the AR remains in the functionally activated (agonistic) state. The simulations on a drug resistance mutant F876L bound to enzalutamide demonstrated that the mutation stabilizes the agonistic conformation of AR LBD, which compromises the efficacy of the antagonists. Principal component analysis (PCA) of the structural fluctuations shows that the binding of enzalutamide and apalutamide induce conformational fluctuations in the AR, which are markedly different from those caused by the agonist as well as another antagonist, bicalutamide. These fluctuations could only be observed with the use of aMD.

Indexed as

Androgen Receptor AntagonistsAndrogensAnilidesBenzamidesBinding SitesDihydrotestosteroneHumansImidazolesLigandsMolecular ConformationMolecular Dynamics SimulationNitrilesPhenylthiohydantoinPrincipal Component AnalysisProtein BindingProtein ConformationAndrogen Receptor AntagonistsAndrogensAnilidesapalutamideAR protein, humanBenzamidesbicalutamideDihydrotestosteroneenzalutamideImidazolesLigandsNitrilesPhenylthiohydantoinReceptors, AndrogenRU 59063ThiohydantoinsTosyl Compounds

Identifiers

PMID34354111
PMCPMC8342701
OpenAlexW3187519263

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.