Evidence map›Paper›PMID 41402853›Full record

ArticleBMC biology2025

Prostate cancer risk-associated single-nucleotide polymorphisms impact the conformational dynamics of prostate-specific antigen.

Srilakshmi Srinivasan, Brooke K Hayes, Mauricio G S Costa, Blake T Riley, Emily Wilson, Emilia M Marijanovic, Itamar Kass, Hannu Koistinen, David E Hoke, Judith Clements and 2 more

Abstract read
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In one paragraph

Article in BMC biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

12 authors.

Srilakshmi Srinivasan *School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
Brooke K Hayes *Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Mauricio G S Costa *Programa de Computação Científica, Fundação Oswaldo Cruz. Av. Brasil , Rio de Janeiro, 4365. 21040-900, Brazil.
Blake T RileyBiomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Emily WilsonBiomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Emilia M MarijanovicBiomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Itamar KassBiomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Hannu KoistinenDepartment of Clinical Chemistry and Haematology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
David E HokeBiomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Judith ClementsSchool of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
Ashley M Buckle *Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Jyotsna Batra *School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia. jbatra@bond.edu.au.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundTwo non-synonymous single-nucleotide polymorphisms (SNPs) rs61752561 (D95N substitution) and rs17632542 (I163T substitution) in the KLK3 gene encoding prostate-specific antigen (PSA), a chymotrypsin-like serine protease, are associated with prostate cancer risk and have been shown to reduce the activity of PSA. However, the structural impact of these SNPs on PSA, which may underlie the observed risk associations and functional alterations, has not been fully explored.

resultsComputational modelling predicted that the variants D95N and I163T do not cause drastic structural changes in PSA. However, molecular dynamics simulations suggested that while the two prominent loops of wild-type PSA remain tethered to their initial conformations over 500 ns of simulation, they are disrupted in both variants, leading to increased loop dynamics. Frustration analysis, normal mode analysis (NMA) and perturbation response scanning identified dynamic links between mutation sites and increased loop dynamics that trigger long-range conformational changes, disrupting the active site and potentially hindering catalytic activity. Thermal denaturation stability assays using recombinant protein show the impact of D95N and I163T substitution on the protein stability.

conclusionsThese data show that KLK3 SNPs disrupt dynamic communication of the key loops required for proteolytic activity of PSA, which may explain the association of these SNPs with prostate cancer risk and/or progression.

Indexed as

Genetic Predisposition to DiseaseKallikreinsPolymorphism, Single NucleotideProstate-Specific AntigenProstatic NeoplasmsHumansMaleMolecular Dynamics SimulationProtein ConformationKallikreinsProstate-Specific AntigenConformational dynamicsKallikrein-related peptidaseMolecular dynamic simulationsProstate cancerProstate-specific antigenProtein stabilitySingle-nucleotide polymorphism

Identifiers

PMID41402853
PMCPMC12821267

What Socratic holds

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LicenceCC BY-NC-ND
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Registered trials

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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 Socratic graph.