Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Liu, Chang; Li, Zhizhen; Liu, Zong-Han; Yang, Shi-Ye; Wang, Qing; Chai, Zong‐Tao

doi:10.3389/fmolb.2022.901603

Cited by 6 publications

(5 citation statements)

References 69 publications

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“…This led us to infer that the inward movement of the P-loop in the FGFR2-38 complex promoted the binding of the inhibitor to the protein. Based on previous studies, despite being rare, similar P-loop closed conformations have been found in some kinase-inhibitor complexes to accommodate the substrate [ 36 , 37 , 38 ]. Statistical analyses of the crystal structure of kinases indicated that inhibitors able to induce the P-loop closed conformation tend to be more selective and highly potent [ 33 ].…”

Section: Resultsmentioning

confidence: 86%

Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation

Zhang

Yasen

et al. 2023

Molecules

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Fibroblast growth factor receptors (FGFRs) play critical roles in the regulation of cell growth, differentiation, and proliferation. Specifically, FGFR2 gene amplification has been implicated in gastric and breast cancer. Pan-FGFR inhibitors often cause large toxic side effects, and the highly conserved ATP-binding pocket in the FGFR1/2/3 isoforms poses an immense challenge in designing selective FGFR2 inhibitors. Recently, an indazole-based inhibitor has been discovered that can selectively target FGFR2. However, the detailed mechanism involved in selective inhibition remains to be clarified. To this end, we performed extensive molecular dynamics simulations of the apo and inhibitor-bound systems along with multiple analyses, including Markov state models, principal component analysis, a cross-correlation matrix, binding free energy calculation, and community network analysis. Our results indicated that inhibitor binding induced the phosphate-binding loop (P-loop) of FGFR2 to switch from the open to the closed conformation. This effect enhanced extensive hydrophobic FGFR2-inhibitor contacts, contributing to inhibitor selectivity. Moreover, the key conformational intermediate states, dynamics, and driving forces of this transformation were uncovered. Overall, these findings not only provided a structural basis for understanding the closed P-loop conformation for therapeutic potential but also shed light on the design of selective inhibitors for treating specific types of cancer.

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Section: Resultsmentioning

confidence: 86%

Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation

Zhang

Yasen

et al. 2023

Molecules

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“…To unveil the dynamic variation of STK17B and STK17A, the inter-residue correlations were analyzed using the dynamical cross-correlation matrix (DCCM) calculations [ 20 , 29 , 30 ]. Correlation coefficients ( CC ij ) between every two Cα atoms ( i and j ) were calculated using all snapshots from four replicas, which showed the relationship among the spatially different domains in both the WT and Q597A mutant systems.…”

Section: Resultsmentioning

confidence: 99%

“…PKIS43 binds to the ATP-binding site of STK17B and interacts with both the N- and C-lobes of the kinase ( Figure 1 B,C). In a recent study, we have used multi-microsecond-length molecular-dynamics (MD) simulations of STK17B in three different states (ligand-free, ADP-bound, and ligand-bound states) to uncover the conformational plasticity of the phosphate-binding loop (P-loop) [ 20 ]. However, how the P-loop of STK17B and STK17A affects inhibitor selectivity is still unexplored.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A

Liu

Zhang

et al. 2022

Molecules

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As a member of the death-associated protein kinase (DAPK) family, STK17B plays an important role in the regulation of cellular apoptosis and has been considered as a promising drug target for hepatocellular carcinoma. However, the highly conserved ATP-binding site of protein kinases represents a challenge to design selective inhibitors for a specific DAPK isoform. In this study, molecular docking, multiple large-scale molecular dynamics (MD) simulations, and binding free energy calculations were performed to decipher the molecular mechanism of the binding selectivity of PKIS43 toward STK17B against its high homology STK17A. MD simulations revealed that STK17A underwent a significant conformational arrangement of the activation loop compared to STK17B. The binding free energy predictions suggested that the driving force to control the binding selectivity of PKIS43 was derived from the difference in the protein–ligand electrostatic interactions. Furthermore, the per-residue free energy decomposition unveiled that the energy contribution from Arg41 at the phosphate-binding loop of STK17B was the determinant factor responsible for the binding specificity of PKIS43. This study may provide useful information for the rational design of novel and potent selective inhibitors toward STK17B.

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“…To further quantitatively assess the energetics of the DAPK1–CaM interactions in the three different systems, the molecular mechanics and generalized Born surface area (MM/GBSA) binding free energy calculations were performed [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. As shown in Table 1 , the binding free energies for the WT, W305Y, and W305D systems were −116.44 ± 15.60, −118.77 ± 16.86, and −92.38 ± 17.54 kcal/mol, respectively.…”

Section: Resultsmentioning

confidence: 99%

Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction

Zhu

Gao

et al. 2022

Biomolecules

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Death-associated protein kinase 1 (DAPK1), as a calcium/calmodulin (CaM) regulated serine/threonine kinase, functions in apoptotic and autophagy pathways and represents an interesting drug target for inflammatory bowel disease and Alzheimer’s disease. The crystal structure of the DAPK1 catalytic domain and the autoregulatory domain (ARD) in complex with CaM provides an understanding of CaM-dependent regulation of DAPK1 activity. However, the molecular basis of how distinct Trp305 (W305Y and W305D) mutations in the ARD modulate different DAPK1 activities remains unknown. Here, we performed multiple, μs-length molecular dynamics (MD) simulations of the DAPK1–CaM complex in three different (wild-type, W305Y, and W305D) states. MD simulations showed that the overall structural complex did not change significantly in the wild-type and W305Y systems, but underwent obvious conformational alteration in the W305D system. Dynamical cross-correlation and principal component analyses revealed that the W305D mutation enhanced the anti-correlated motions between the DAPK1 and CaM and sampled a broader distribution of conformational space relative to the wild-type and W305Y systems. Structural and energetical analyses further exhibited that CaM binding was unfavored in response to the W305D mutation, resulting in the decreased binding of CaM to the W305D mutant. Furthermore, the hydrogen bonds and salt bridges responsible for the loss of CaM binding on the interface of the DAPK1–CaM complex were identified in the W305D mutant. This result may provide insights into the key role of Trp305 in the regulation of CaM-mediated DAPK1 activity.

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Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Cited by 6 publications

References 69 publications

Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation

Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation

Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A

Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction

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