Heat shock protein 90 is a valuable target for anticancer drugs because of its role in the activation and stabilization of multiple oncogenic signalling proteins. While several compounds inhibit heat shock protein 90 by binding the N-terminal domain, recent studies have proved that the C-terminal domain is important for dimerization of the chaperone and contains an additional binding site for inhibitors. Heat shock protein 90 inhibition achieved with molecules binding to the C-terminal domain provides an additional and novel opportunity to design and develop drugs. Therefore, for the first time, we have investigated the structure and the dynamic behaviour of the C-terminal domain of human heat shock protein 90 with and without the small-middle domain, using homology modelling and molecular dynamics simulations. In addition, secondary structure predictions and peptide folding simulations proved useful to investigate a putative additional alpha-helix located between H18 and beta20 of the C-terminal domain. Finally, we used the structural information to infer the location of the binding site located in the C-terminal domain by using a number of computational tools. The predicted pocket is formed by two grooves located between helix H18, the loop downstream of H18 and the loop connecting helices H20 and H21 of each monomer of the C-terminal domain, with only two amino acids contributing from each middle domain.

Structural models and binding site prediction of the C-terminal domain of human Hsp90: a new target for anticancer drugs / Sgobba, Miriam; Degliesposti, Gianluca; A. M., Ferrari; Rastelli, Giulio. - In: CHEMICAL BIOLOGY & DRUG DESIGN. - ISSN 1747-0277. - STAMPA. - 71:(2008), pp. 420-433. [10.1111/j.1747-0285.2008.00650.x]

Structural models and binding site prediction of the C-terminal domain of human Hsp90: a new target for anticancer drugs

SGOBBA, Miriam;DEGLIESPOSTI, Gianluca;RASTELLI, Giulio
2008

Abstract

Heat shock protein 90 is a valuable target for anticancer drugs because of its role in the activation and stabilization of multiple oncogenic signalling proteins. While several compounds inhibit heat shock protein 90 by binding the N-terminal domain, recent studies have proved that the C-terminal domain is important for dimerization of the chaperone and contains an additional binding site for inhibitors. Heat shock protein 90 inhibition achieved with molecules binding to the C-terminal domain provides an additional and novel opportunity to design and develop drugs. Therefore, for the first time, we have investigated the structure and the dynamic behaviour of the C-terminal domain of human heat shock protein 90 with and without the small-middle domain, using homology modelling and molecular dynamics simulations. In addition, secondary structure predictions and peptide folding simulations proved useful to investigate a putative additional alpha-helix located between H18 and beta20 of the C-terminal domain. Finally, we used the structural information to infer the location of the binding site located in the C-terminal domain by using a number of computational tools. The predicted pocket is formed by two grooves located between helix H18, the loop downstream of H18 and the loop connecting helices H20 and H21 of each monomer of the C-terminal domain, with only two amino acids contributing from each middle domain.
71
420
433
Structural models and binding site prediction of the C-terminal domain of human Hsp90: a new target for anticancer drugs / Sgobba, Miriam; Degliesposti, Gianluca; A. M., Ferrari; Rastelli, Giulio. - In: CHEMICAL BIOLOGY & DRUG DESIGN. - ISSN 1747-0277. - STAMPA. - 71:(2008), pp. 420-433. [10.1111/j.1747-0285.2008.00650.x]
Sgobba, Miriam; Degliesposti, Gianluca; A. M., Ferrari; Rastelli, Giulio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/612461
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