From Determinants of RUNX1/ETO Tetramerization to Small-Molecule Protein–Protein Interaction Inhibitors Targeting Acute Myeloid Leukemia

Metz, A.; Schanda, Julia; Grez, Manuel; Wichmann, Christian; Gohlke, Holger

doi:10.1021/ci400332e

Cited by 24 publications

(50 citation statements)

References 42 publications

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“…Mimicking localized interactions in hot spot regions by small molecules has been found as a viable way to interfere with PPIs [4], [11], [12], [67]–[69]. Regarding the physicochemical properties of our hot spots, the predominantly hydrophobic character is in line with the rule of four [70], a characterization of the chemical space of PPI inhibitors, which suggests that inhibitors should have log P>4.…”

Section: Discussionmentioning

confidence: 70%

“…The approach mimics computational alanine scanning and has been applied successfully by us in retro- and prospective studies on the determinants of protein-protein interactions [10]–[12], [45]. The results reveal a distinctive interaction profile, which is almost identical for the two monomers (Figure 2, A).…”

Section: Resultsmentioning

confidence: 99%

“…Identifying hot spots in protein-protein interfaces yields insights into the energetics of PPIs that can be exploited for the identification of PPI modulators [10]–[12], [45], [51]. Here, we aimed at identifying hot spot residues that determine the stability of the hHsp90 CTD dimer following the idea that inhibiting CTD dimerization should provide a novel way to therapeutically interfere with Hsp90 activity.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, PPI modulators often target only the functional epitope that contains these hot spots [11]–[13]. Thus, identifying such hot spots provides important insights into the energetics of PPIs, which can be exploited for the identification of PPI modulators [12].…”

Section: Introductionmentioning

confidence: 99%

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Resolving Hot Spots in the C-Terminal Dimerization Domain that Determine the Stability of the Molecular Chaperone Hsp90

et al. 2014

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Human heat shock protein of 90 kDa (hHsp90) is a homodimer that has an essential role in facilitating malignant transformation at the molecular level. Inhibiting hHsp90 function is a validated approach for treating different types of tumors. Inhibiting the dimerization of hHsp90 via its C-terminal domain (CTD) should provide a novel way to therapeutically interfere with hHsp90 function. Here, we predicted hot spot residues that cluster in the CTD dimerization interface by a structural decomposition of the effective energy of binding computed by the MM-GBSA approach and confirmed these predictions using in silico alanine scanning with DrugScorePPI. Mutation of these residues to alanine caused a significant decrease in the melting temperature according to differential scanning fluorimetry experiments, indicating a reduced stability of the mutant hHsp90 complexes. Size exclusion chromatography and multi-angle light scattering studies demonstrate that the reduced stability of the mutant hHsp90 correlates with a lower complex stoichiometry due to the disruption of the dimerization interface. These results suggest that the identified hot spot residues can be used as a pharmacophoric template for identifying and designing small-molecule inhibitors of hHsp90 dimerization.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Resolving Hot Spots in the C-Terminal Dimerization Domain that Determine the Stability of the Molecular Chaperone Hsp90

et al. 2014

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“…5 One of these compounds, 7.44, was of particular interest as it showed biological activity in vitro and in vivo.…”

Section: A B C E D F G H Imentioning

confidence: 99%

Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization

et al. 2017

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Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

et al. 2019

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We describe the first extensive energetic evaluation of GPCR dimerization on the atomistic level by means of potential of mean force (PMF) computations and implicit solvent/implicit membrane end‐point free energy calculations (MM‐PBSA approach). Free energies of association computed from the PMFs show that the formation of both the 1/8 and 4/5 interface is energetically favorable for TGR5, the first GPCR known to be activated by hydrophobic bile acids and neurosteroids. Furthermore, formation of the 1/8 interface is favored over that of the 4/5 interface. Both results are in line with our previous FRET experiments in live cells. Differences in lipid‐protein interactions are identified to contribute to the observed differences in free energies of association. A per‐residue decomposition of the MM‐PBSA effective binding energy reveals hot spot residues specific for both interfaces that form clusters. This knowledge may be used to guide the design of dimerization inhibitors or perform mutational studies to explore physiological consequences of distorted TGR5 association. Finally, we characterized the role of Y111, located in the conserved (D/E)RY motif, as a facilitator of TGR5 interactions. The types of computations performed here should be transferable to other transmembrane proteins that form dimers or higher oligomers as long as good structural models of the dimeric or oligomeric states are available. Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse‐grained level. © 2019 Wiley Periodicals, Inc.

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From Determinants of RUNX1/ETO Tetramerization to Small-Molecule Protein–Protein Interaction Inhibitors Targeting Acute Myeloid Leukemia

Cited by 24 publications

References 42 publications

Resolving Hot Spots in the C-Terminal Dimerization Domain that Determine the Stability of the Molecular Chaperone Hsp90

Resolving Hot Spots in the C-Terminal Dimerization Domain that Determine the Stability of the Molecular Chaperone Hsp90

Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

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