Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133
Objective·To explore the mechanism at the atomic level by which the KRASG12D/R68G mutation induces tumor cell resistance to MRTX1133.Methods·The crystal structure data of the KRASG12D-MRTX1133 complex were obtained from the RCSB Protein Data Bank (PDB). PyMOL software was used to mutate arginine at...
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Editorial Office of Journal of Shanghai Jiao Tong University (Medical Science)
2025-06-01
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| Series: | Shanghai Jiaotong Daxue xuebao. Yixue ban |
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| Online Access: | https://xuebao.shsmu.edu.cn/article/2025/1674-8115/1674-8115-2025-45-6-705.shtml |
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| author | WANG Gaoming CUI Ran LI Yanjing LIU Yingbin |
| author_facet | WANG Gaoming CUI Ran LI Yanjing LIU Yingbin |
| author_sort | WANG Gaoming |
| collection | DOAJ |
| description | Objective·To explore the mechanism at the atomic level by which the KRASG12D/R68G mutation induces tumor cell resistance to MRTX1133.Methods·The crystal structure data of the KRASG12D-MRTX1133 complex were obtained from the RCSB Protein Data Bank (PDB). PyMOL software was used to mutate arginine at position 68 of KRAS to glycine (R68G), constructing the initial conformations of the KRASG12D-MRTX1133 and KRASG12D/R68G-MRTX1133 complexes. The LEaP module was used to build simulation systems under periodic boundary conditions. The ff19SB force field was applied to standard amino acids in KRAS, GAFF (general AMBER force field) to MRTX1133, and TIP3P (intermolecular potential three point) to water molecules. Energy minimization was performed using the Amber software suite. The systems were then heated to 300 K, followed by NVT (constant volume and temperature) equilibration and NPT (constant pressure and temperature) production. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), principal component analysis (PCA) and solvent-accessible surface area (SASA) of MRTX1133 and GDP were analyzed using cpptraj. The number of hydrogen bonds between regions and the dynamic cross-correlation matrix (DCCM) of amino acid movements were also calculated.Results·RMSD analysis showed greater structural variation in KRAS in the KRASG12D/R68G system compared to the KRASG12D system. RMSF analysis revealed significantly higher fluctuations in the Switch Ⅰ and Switch Ⅱ regions of the KRASG12D/R68G system. PCA indicated that Switch Ⅰ and Switch Ⅱ in the KRASG12D/R68G system were more frequently in an open conformation. The distances between Switch Ⅰ and the P-loop, and between Switch Ⅱ and the P-loop, were larger in the KRASG12D/R68G system, indicating an expanded binding pocket for GDP and MRTX1133 compared to the KRASG12D system. SASA analysis indicated that both GDP and MRTX1133 had increased solvent exposure in the KRASG12D/R68G system. DCCM analysis revealed more decoupled movements among the Switch Ⅰ, Switch Ⅱ and P-loop regions in the KRASG12D/R68G system.Conclusion·The KRASG12D/R68G mutation disrupts the interactions between the Switch Ⅰ and Switch Ⅱ regions, leading to their separation and the opening of the MRTX1133 binding pocket. This increases the solvent exposure of MRTX1133, accelerates its dissociation, and ultimately results in KRASG12D/R68G resistance to MRTX1133. |
| format | Article |
| id | doaj-art-4de51e2e7b924f389cd5bbd288427521 |
| institution | DOAJ |
| issn | 1674-8115 |
| language | zho |
| publishDate | 2025-06-01 |
| publisher | Editorial Office of Journal of Shanghai Jiao Tong University (Medical Science) |
| record_format | Article |
| series | Shanghai Jiaotong Daxue xuebao. Yixue ban |
| spelling | doaj-art-4de51e2e7b924f389cd5bbd2884275212025-08-20T02:44:52ZzhoEditorial Office of Journal of Shanghai Jiao Tong University (Medical Science)Shanghai Jiaotong Daxue xuebao. Yixue ban1674-81152025-06-0145670571610.3969/j.issn.1674-8115.2025.06.0051674-8115（2025）06-0705-12Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133WANG Gaoming0CUI Ran1LI Yanjing2LIU Yingbin3Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, ChinaDepartment of Hepatopancreatobiliary Surgery, East Hospital Affiliated Tongji University, Shanghai 200120, ChinaState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, ChinaDepartment of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, ChinaObjective·To explore the mechanism at the atomic level by which the KRASG12D/R68G mutation induces tumor cell resistance to MRTX1133.Methods·The crystal structure data of the KRASG12D-MRTX1133 complex were obtained from the RCSB Protein Data Bank (PDB). PyMOL software was used to mutate arginine at position 68 of KRAS to glycine (R68G), constructing the initial conformations of the KRASG12D-MRTX1133 and KRASG12D/R68G-MRTX1133 complexes. The LEaP module was used to build simulation systems under periodic boundary conditions. The ff19SB force field was applied to standard amino acids in KRAS, GAFF (general AMBER force field) to MRTX1133, and TIP3P (intermolecular potential three point) to water molecules. Energy minimization was performed using the Amber software suite. The systems were then heated to 300 K, followed by NVT (constant volume and temperature) equilibration and NPT (constant pressure and temperature) production. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), principal component analysis (PCA) and solvent-accessible surface area (SASA) of MRTX1133 and GDP were analyzed using cpptraj. The number of hydrogen bonds between regions and the dynamic cross-correlation matrix (DCCM) of amino acid movements were also calculated.Results·RMSD analysis showed greater structural variation in KRAS in the KRASG12D/R68G system compared to the KRASG12D system. RMSF analysis revealed significantly higher fluctuations in the Switch Ⅰ and Switch Ⅱ regions of the KRASG12D/R68G system. PCA indicated that Switch Ⅰ and Switch Ⅱ in the KRASG12D/R68G system were more frequently in an open conformation. The distances between Switch Ⅰ and the P-loop, and between Switch Ⅱ and the P-loop, were larger in the KRASG12D/R68G system, indicating an expanded binding pocket for GDP and MRTX1133 compared to the KRASG12D system. SASA analysis indicated that both GDP and MRTX1133 had increased solvent exposure in the KRASG12D/R68G system. DCCM analysis revealed more decoupled movements among the Switch Ⅰ, Switch Ⅱ and P-loop regions in the KRASG12D/R68G system.Conclusion·The KRASG12D/R68G mutation disrupts the interactions between the Switch Ⅰ and Switch Ⅱ regions, leading to their separation and the opening of the MRTX1133 binding pocket. This increases the solvent exposure of MRTX1133, accelerates its dissociation, and ultimately results in KRASG12D/R68G resistance to MRTX1133.https://xuebao.shsmu.edu.cn/article/2025/1674-8115/1674-8115-2025-45-6-705.shtmlmrtx1133kras secondary mutationmolecular dynamics simulationresistance mechanism |
| spellingShingle | WANG Gaoming CUI Ran LI Yanjing LIU Yingbin Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133 Shanghai Jiaotong Daxue xuebao. Yixue ban mrtx1133 kras secondary mutation molecular dynamics simulation resistance mechanism |
| title | Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133 |
| title_full | Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133 |
| title_fullStr | Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133 |
| title_full_unstemmed | Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133 |
| title_short | Study on the mechanism of KRAS R68G secondary mutation-induced resistance to KRASG12D-targeted inhibitor MRTX1133 |
| title_sort | study on the mechanism of kras r68g secondary mutation induced resistance to krasg12d targeted inhibitor mrtx1133 |
| topic | mrtx1133 kras secondary mutation molecular dynamics simulation resistance mechanism |
| url | https://xuebao.shsmu.edu.cn/article/2025/1674-8115/1674-8115-2025-45-6-705.shtml |
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