Molecular insight into γ–γ tubulin lateral interactions within the γ-tubulin ring complex (γ-TuRC)

Suri, Charu; Hendrickson, Triscia W.; Joshi, Harish C.; Naik, Pradeep Kumar

doi:10.1007/s10822-014-9779-2

Cited by 21 publications

(32 citation statements)

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“…In contrast, the decomposition of binding free energy calculated on the basis of MM‐PBSA into per residue basis was not so far possble because PB nonpolar solvation energies are currently not decomposable using Amber simulation package. Similar studies have been reported earlier in the insulin dimer, TCR‐p‐MHC, Ras‐Raf, and Ras‐RalGDS complexes and γ‐γ tubulin dimers . The results from these studies demonstrated good correlations between the calculated per residue binding free energy and the experimental binding free energies differences for the alanine mutants.…”

Section: Resultssupporting

confidence: 87%

“…Similar studies have been reported earlier in the insulin dimer, 53 TCR-p-MHC, 54 Ras-Raf, and Ras-RalGDS 55 complexes and g-g tubulin dimers. 56 The results from these studies demonstrated good correlations between the calculated per residue binding free energy and the experimental binding free energies differences for the alanine mutants. Toward this end the predictive binding energy (DG bind,GB ) between GCP4 and g-tubulin was decomposed into contributions from the residues of the two partners.…”

Section: Per Residue Energy Contribution To the Binding Free Energymentioning

confidence: 69%

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Molecular modeling reveals binding interface of γ-tubulin with GCP4 and interactions with noscapinoids

2015

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The initiation of microtubule assembly within cells is guided by a cone shaped multi-protein complex, γ-tubulin ring complex (γTuRC) containing γ-tubulin and atleast five other γ-tubulin-complex proteins (GCPs), i.e., GCP2, GCP3, GCP4, GCP5, and GCP6. The rim of γTuRC is a ring of γ-tubulin molecules that interacts, via one of its longitudinal interfaces, with GCP2, GCP3, or GCP4 and, via other interface, with α/β-tubulin dimers recruited for the microtubule lattice formation. These interactions however, are not well understood in the absence of crystal structure of functional reconstitution of γTuRC subunits. In this study, we elucidate the atomic interactions between γ-tubulin and GCP4 through computational techniques. We simulated two complexes of γ-tubulin-GCP4 complex (we called dimer1 and dimer2) for 25 ns to obtain a stable complex and calculated the ensemble average of binding free energies of -158.82 and -170.19 kcal/mol for dimer1 and -79.53 and -101.50 kcal/mol for dimer2 using MM-PBSA and MM-GBSA methods, respectively. These highly favourable binding free energy values points to very robust interactions between GCP4 and γ-tubulin. From the results of the free-energy decomposition and the computational alanine scanning calculation, we identified the amino acids crucial for the interaction of γ-tubulin with GCP4, called hotspots. Furthermore, in the endeavour to identify chemical leads that might interact at the interface of γ-tubulin-GCP4 complex; we found a class of compounds based on the plant alkaloid, noscapine that binds with high affinity in a cavity close to γ-tubulin-GCP4 interface compared with previously reported compounds. All noscapinoids displayed stable interaction throughout the simulation, however, most robust interaction was observed for bromo-noscapine followed by noscapine and amino-noscapine. This offers a novel chemical scaffold for γ-tubulin binding drugs near γ-tubulin-GCP4 interface.

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Section: Resultssupporting

confidence: 87%

Section: Per Residue Energy Contribution To the Binding Free Energymentioning

confidence: 69%

Molecular modeling reveals binding interface of γ-tubulin with GCP4 and interactions with noscapinoids

2015

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“…After understanding the dynamic properties of P5091 at all different sites, we calculatedthe free energy of binding ( Δ G bind ) [ 32 – 34 ]. The results indicate that P5091 binds more favorably at S7 ( Δ G bind = −34.23 kcal/mol) than S4 ( Δ G bind = −19.84 kcal/mol) ( Supplementary Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics simulation reveals the possible druggablehot-spotsof USP7

et al. 2018

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The plasticity in Ubiquitin Specific Proteases (USP7) inducing conformational changes at important areas has highlighted an intricate mechanism, by which USP7 is regulated. Given the importance of USP7 in oncogenic pathways and immune-oncology, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, the discovery of deubiquitinases (DUBs) inhibitors, knowledge of their binding site and understanding the possible mechanism of action has proven particularly challenging. We disclose the most likely binding site of P5091 (a potent USP7 inhibitor), which reveal a cryptic allosteric site through extensive computational studies in an inhibitor dependent and independent manner. Overall, these findings demonstrate the tractability and druggability of USP7. Through a series of molecular dynamics simulations and detailed quantitative analysis, a dynamically stable allosteric binding site near catalytic center of the inactive state of USP7 (site partially absent in active state), along with two newly identified sites have been revealed, which opens the avenue for rational structure-guided inhibitor designing in USP7 specific-manner.

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“…Positive values of △△G bind indicate the corresponding residue provides the favorable contribution, while negative values suggest the related residue produces unfavorable contribution …”

Section: Methodsmentioning

confidence: 99%

Identification of the active site of human mitochondrial malonyl‐coenzyme a decarboxylase: A combined computational study

Ling

Liu

et al. 2016

Proteins

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Malonyl-CoA decarboxylase (MCD) can control the level of malonyl-CoA in cell through the decarboxylation of malonyl-CoA to acetyl-CoA, and plays an essential role in regulating fatty acid metabolism, thus it is a potential target for drug discovery. However, the interactions of MCD with CoA derivatives are not well understood owing to unavailable crystal structure with a complete occupancy in the active site. To identify the active site of MCD, molecular docking and molecular dynamics simulations were performed to explore the interactions of human mitochondrial MCD (HmMCD) and CoA derivatives. The findings reveal that the active site of HmMCD indeed resides in the prominent groove which resembles that of CurA. However, the binding modes are slightly different from the one observed in CurA due to the occupancy of the side chain of Lys183 from the N-terminal helical domain instead of the adenine ring of CoA. The residues 300 - 305 play an essential role in maintaining the stability of complex mainly through hydrogen bond interactions with the pyrophosphate moiety of acetyl-CoA. Principle component analysis elucidates the conformational distribution and dominant concerted motions of HmMCD. MM_PBSA calculations present the crucial residues and the major driving force responsible for the binding of acetyl-CoA. These results provide useful information for understanding the interactions of HmMCD with CoA derivatives. Proteins 2016; 84:792-802. © 2016 Wiley Periodicals, Inc.

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Molecular insight into γ–γ tubulin lateral interactions within the γ-tubulin ring complex (γ-TuRC)

Cited by 21 publications

References 50 publications

Molecular modeling reveals binding interface of γ-tubulin with GCP4 and interactions with noscapinoids

Molecular modeling reveals binding interface of γ-tubulin with GCP4 and interactions with noscapinoids

Molecular dynamics simulation reveals the possible druggablehot-spotsof USP7

Identification of the active site of human mitochondrial malonyl‐coenzyme a decarboxylase: A combined computational study

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