Understanding ligand-based modulation of the Hsp90 molecular chaperone dynamics at atomic resolution

Colombo, Giorgio; Morra, Giulia; Meli, Massimiliano; Verkhivker, Gennady M.

doi:10.1073/pnas.0802879105

Cited by 77 publications

(80 citation statements)

References 41 publications

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“…Molecular dynamics simulations also show a loss of lid structure for hHsp90 when ATP is bound. The lid loses α-helical content and gains flexibility as a consequence of interactions with the nucleotide (Colombo et al, 2008). This is in contrast to other GHKL family members such as MutL where the lid becomes more ordered in the presence of nucleotide (Ban et al, 1999).…”

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 89%

“…Simulations also show that local conformational changes in the lid region are coupled to larger conformational changes. While the lid becomes more flexible upon the binding of ATP, Essential Dynamics and Covariance analysis of the simulations shows that the rest of the NTD becomes more constrained with a stronger interaction network across the entire NTD (Colombo et al, 2008).…”

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 98%

“…The largest local changes occur in the lid (residues 94-124, Hsp82 numbering, Figure 1, purple) which consists of a helix-loop-helix positioned near the binding pocket and these motions communicate the nucleotide state of Hsp90 to the rest of the protein especially the domain interfaces. Crystal structures have revealed that the lid is highly variable in its orientation, and molecular dynamics simulations with the human NTD confirm that the most significant local changes upon nucleotide binding involve the lid (Colombo et al, 2008). In one orientation seen in cytosolic human Hsp90 (hHsp90) loop 2 of the lid (L2, see Figure 4A, blue) is displaced by more than 9Å into the nucleotide binding pocket potentially blocking the binding of ligand (Stebbins et al, 1997).…”

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 99%

“…MD simulations of the NTD showed that the lid spontaneously converts from the nucleotide free conformation to the nucleotide bound conformation (Colombo et al, 2008) suggesting that a continuum of conformations may exist and nucleotide serves to stabilize one conformation over another. Kinetic studies provided the first biochemical evidence that Hsp90 exists as a mixture of states in the presence of nucleotide and the relative amounts of different conformations is homolog specific.…”

Section: Hsp90 Exists In a Dynamic Equilibrium Between Conformationalmentioning

confidence: 99%

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Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

282

262

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 89%

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 98%

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 99%

Section: Hsp90 Exists In a Dynamic Equilibrium Between Conformationalmentioning

confidence: 99%

See 2 more Smart Citations

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

282

262

View full text Add to dashboard Cite

show abstract

“…Computational methods, mainly based on all-atom Molecular Dynamics simulations, now offer unprecedented possibilities to design molecules and pharmacophore models that target flexible receptors, taking multiple different conformational states available on the protein's energy landscape. Including an atomic level resolution description of the adaptation of the two binding partners to each other and/or differences in the solution behavior compared to the X-ray situation in the small molecule selection process has the potential to extend the chemical space of PPI inhibitors suggesting new structures, chemotypes and ultimately drugs [62][63][64].…”

Section: Exploiting Protein-protein Interactions In Drug Discoverymentioning

confidence: 99%

Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors

et al. 2010

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AbstrAct:Inhibitors of angiogenesis are an important addition to conventional chemotherapy. Among different "druggable" angiogenic factors, fibroblast growth factor-2 (FGF-2) is an attractive target for novel therapies because of its intricated involvement in tumor neovascularization, tumor cell proliferation and migration, and the acquisition of resistance to antiangiogenic therapies. FGF-2 bioavailability and activity is affected by several natural ligands, including the endogenous inhibitor of angiogenesis thrombospondin-1 (TSP-1). We hypothesized that the FGF-2-binding sequence of TSP-1 might serve as a template for the development of non-peptide inhibitors of angiogenesis. Computational biology and nuclear magnetic resonance spectroscopy approaches, major investigative tools in the characterizations of protein-protein interaction (PPI), were used to map the residues at the TSP-1/FGF-2 interface. The translation of this three-dimensional information into a pharmacophore model allowed screening a small molecule databases, identifying three FGF-2-binding, antiangiogenic small molecules, mimetic of TSP-1. Pharmacophore-based approaches are thus feasible tools to exploit naturally occurring PPI, by generating a set of lead compounds mimetic of endogenous proteins, as a starting point for the development of novel therapeutic agents.

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Water Networks Repopulate Protein–Ligand Interfaces with Temperature

et al. 2022

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High-resolution crystal structures highlight the importance of water networks in protein-ligand interactions. However, as these are typically determined at cryogenic temperature, resulting insights may be structurally precise but not biologically accurate. By collecting 10 matched room-temperature and cryogenic datasets of the biomedical target Hsp90α, we identified changes in water networks that impact protein conformations at the ligand binding interface. Water repositioning with temperature repopulates protein ensembles and ligand interactions. We introduce Flipper conformational barcodes to identify temperature-sensitive regions in electron density maps. This revealed that temperature-responsive states coincide with ligand-responsive regions and capture unique binding signatures that disappear upon cryo-cooling. Our results have implications for discovering Hsp90 selective ligands, and, more generally, for the utility of hidden protein and water conformations in drug discovery.

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Understanding ligand-based modulation of the Hsp90 molecular chaperone dynamics at atomic resolution

Cited by 77 publications

References 41 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors

Water Networks Repopulate Protein–Ligand Interfaces with Temperature

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