First Structural View of a Peptide Interacting with the Nucleotide Binding Domain of Heat Shock Protein 90

Abstract

The involvement of Hsp90 in progression of diseases like cancer, neurological disorders and several pathogen related conditions is well established. Hsp90, therefore, has emerged as an attractive drug target for many of these diseases. Several small molecule inhibitors of Hsp90, such as geldanamycin derivatives, that display antitumor activity, have been developed and are under clinical trials. However, none of these tested inhibitors or drugs are peptide-based compounds. Here we report the first crystal structure of a peptide bound at the ATP binding site of the N-terminal domain of Hsp90. The peptide makes several specific interactions with the binding site residues, which are comparable to those made by the nucleotide and geldanamycin. A modified peptide was designed based on these interactions. Inhibition of ATPase activity of Hsp90 was observed in the presence of the modified peptide. This study provides an alternative approach and a lead peptide molecule for the rational design of effective inhibitors of Hsp90 function.

Identification of AtHsp90.6 involved in early embryogenesis and its structure prediction by molecular dynamics simulations

“…In the ADP-bound open state of AtHsp90.6N, three different residues, N128, K135 and M175, contributed −4.4, −1.53 and −2.14 kcal mol −1 to the binding energies. The model has a similar binding mode with the crystal structure [38,39], as shown in figure 4 a , b (left and middle panels).

Figure 4.Energy decomposition analysis by MM-GBSA.

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“…This mainly resulted from the various biological functions for L2 and L1/L3. Previous experimental structure [39] suggested two different binding modes of L2 in the ATP- and ADP-bound systems. In the ATP-bound closed state, L2 formed significant interactions with the helix H2, stabilizing ATP in the binding cavity.…”

Proteomic analysis provides integrated insight into mechanisms of Turnip mosaic virus long distance movement in Brassica rapa

“…Heat shock proteins (Hsps) are found to be an important host factor in viral infection. HSP90s (Bra013774) are ubiquitous molecular chaperones that are involved in cell signalling (Pratt et al 2006), protein degradation (Imai et al 2003), hormone reception (Raman et al 2015), as transcription factors and danger signals (Zhu et al 2016). Small heat shock proteins (sHSPs) (Bra000703) are a major family within HSPs with functions resembling that of HSPs (Uversky et al 2005), and sHSPs act as the type of molecular chaperone that contributes to the development of thermotolerance (Waters et al 1996).…”

“…Blocking their function will make the cells less resistant. Some HSP90 inhibitors were proved to be helpful in virus infection (Raman et al 2015). Phosphorylation can regulate HSPs and induce the pathogenesis-related protein genes.…”

Cooperative “folding transition” in the sequence space facilitates function-driven evolution of protein families

“…2B) showed a clear two-state transition between low energy and high energy states. In order to confirm if the low-energy sequences are indeed similar to the natural sequences, we compared the (Mondragon et al, 1989); 4rdu (JCSG and STEMCELL, 2014); 2c2a (Marina et al, 2005); 1l3k (Vitali et al, 2002); 1g9o (Karthikeyan et al, 2001); 2ic2 (McLellan et al, 2006); 1u2h (Manjasetty et al, 2005); 4zhw (Li et al, 2015); 2r5u (Biswas and Tsodikov, 2008); 4unu (Brumshtein et al, 2014); 2nrl (Schreiter et al, 2007); 4xe2 (Raman et al, 2015); 3chy (Volz and Matsumura, 1991). e Disordering temperature.…”