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Background <p>Two non-synonymous single-nucleotide polymorphisms (SNPs) rs61752561 (D95N substitution) and rs17632542 (I163T substitution) in the <i>KLK3</i> 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.</p> Results <p>Computational 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&#xa0;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.</p> Conclusions <p>These data show that <i>KLK3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • 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,
  • Ashley M. Buckle,
  • Jyotsna Batra

摘要

Background

Two 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.

Results

Computational 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.

Conclusions

These 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.