Self-binding peptides: Binding-upon-folding versus folding-upon-binding

Li, Zhongyan; Yan, Fu Gang; Miao, Qingqing; Meng, Yunxiao; Wen, Li; Jiang, Qianhu; Zhou, Peng

doi:10.1016/j.jtbi.2019.02.014

Cited by 68 publications

(22 citation statements)

References 39 publications

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“…The two intramolecular interactions required for TIM auto‐inhibition were defined as self‐binding peptides (SBPs) in previous studies, which can be exploited as therapeutic targets for cancer intervention . We also demonstrated that the TIM auto‐inhibitory state can be relieved by targeting its SH3 domain with rationally designed peptide aptamers, thus indirectly substantiating the dual auto‐inhibition hypothesis described by Yohe et al SH3 domain is a group of small peptide‐recognition modules that can only weakly and transiently interact with natural peptides .…”

Section: Introductionsupporting

confidence: 82%

Exploring the systematic effect of N‐substituted PxxP motifs on peptoid affinity to ARHGEF5/TIM SH3 domain and its relationship with ARHGEF5/TIM activation

Zhou³

et al. 2019

Proteins

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The TIM protein is a short isoform of full-length Rho guanine nucleotide exchange factor 5 (ARHGEF5), which acts as a functional regulator of Rho-dependent signaling pathways by activating the Rho family of GTPases. The activation is auto-inhibited by a putative helix N-terminal to the DH domain of TIM, which is stabilized by the intramolecular interaction of C-terminal SH3 domain with a proline-rich region 47 SSPRQPRKAL 56 (termed as SSP peptide) between the putative helix and the DH domain. Previously, we demonstrate that the auto-inhibitory state of TIM protein can be relieved by targeting its SH3 domain with rationally designed peptide ligands.However, the designed natural peptides have only a moderately increased affinity (~2-fold) as compared to the cognate SH3-SSP interaction and are susceptible to protease degradation. Here, considering that proline is the only endogenous Nsubstituted amino acid that plays a critical role in SH3-peptide recognition, the two key proline residues Pro49 and Pro52 in the core 49 PxxP 52 motif of SSP peptide are systematically replaced by 19 N-substituted amino acid types to derive a variety of nonnatural peptoid ligands for TIM SH3 domain. Dynamics and energetics analyses reveal that the replacement would impair the active polyproline II (PPII) helical conformation of SSP peptide due to lack of structural constraint introduced by the fivemembered ring of native proline side-chains, thus increasing the peptide flexibility that could incur a large entropy penalty upon binding to the domain. However, the impairment is not very significant and the peptide affinity may also be restored and improved if the N-substituted motif of derived peptiod ligands can effectively interact with the PxxP-binding site of TIM SH3 domain. Consequently, a number of potent peptoids are successfully designed by fluorescence spectroscopy confirmation, in which three (ie, SSP[N-Ile49, N-Asn52], SSP[N-Phe49, N-Gln52], and SSP[N-Tyr49, N-Asn52]) exhibit considerably increased affinity (K d = 0.09, 0.07, and 0.04 μM,respectively) relative to the native SSP peptide (K d = 0.87 μM). In addition, guanine nucleotide exchange assays also substantiate that the designed SH3-targeted

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Section: Introductionsupporting

confidence: 82%

Exploring the systematic effect of N‐substituted PxxP motifs on peptoid affinity to ARHGEF5/TIM SH3 domain and its relationship with ARHGEF5/TIM activation

Zhou³

et al. 2019

Proteins

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“…[ 41 ] The calculations characterized vacuum Coulombic energy, nonclassical charge‐transfer effect, and van der Waals potential; a linear combination of the QM and MM energy contributions was utilized to partially remove the double counting of the repulsive van der Waals term. [ 42 ] The solvent contribution and conformational flexibility were calculated by classical continuum medium model and conformational free energy analysis, respectively, [ 43,44 ] which have been found to be compatible with QM/MM‐derived protein–ligand interaction energy. [ 27 ] With this strategy, the binding free energies of a kinase–SSBI complex before (Δ G WT ) and after (Δ G MT ) mutation were readily obtained; thus, the binding energy change upon mutation can be expressed as ΔΔ G = Δ G MT − Δ G WT .…”

Section: Methodsmentioning

confidence: 99%

Systematic response of staurosporine scaffold‐based inhibitors to drug‐resistant cancer kinase mutations

2020

Archiv der Pharmazie

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Human protein kinases have been established as promising druggable targets in cancer therapy. However, a large number of acquired drug-resistant kinase mutations are observed after first-and second-line kinase inhibitor treatments, largely limiting the application of small-molecule inhibitors in the targeted cancer therapy.Previously, the pan-kinase inhibitor staurosporine and its derivatives have been reported to selectively inhibit gatekeeper mutants over wild-type kinases, suggesting that the staurosporine scaffold is potentially helpful in developing wild-typesparing inhibitors of drug-resistant kinase mutants. Here, a systematic response profile of 32 staurosporine scaffold-based inhibitors (SSBIs) for 61 ontologyenriched drug-resistant cancer kinase mutations is created using a combination of in silico analysis and in vitro assay, from which it is possible to identify those mutations that have the potential to cause resistance or confer sensitivity to SSBIs. The profile reveals that SSBIs exhibit distinct responses to kinase gatekeeper and nongatekeeper mutations, and SSBIs bearing p7 substituents can considerably influence their response to kinase gatekeeper mutations, particularly for the mutations of the Ile residue, which possesses a Cβ methyl group that tends to cause steric clash with bound SSBIs. Nongatekeeper mutations generally have a moderate and unfavorable effect on SSBI activity, as most of them are outside the kinase active site and do not directly contact inhibitor ligands. In addition, it is found that resistance is commonly caused by mutation-induced hindrance effects, whereas sensitivity is primarily conferred by mutation-established additional interactions. K E Y W O R D Sdrug-resistant kinase mutation, inhibitor selectivity, protein kinase, staurosporine scaffold-based inhibitor, targeted cancer therapy

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“…Entropy contribution was not considered. [41][42][43] Mutation energy (ΔΔG mtt ) is the energetic effect of an EGFR residue mutation on ATP binding energy (ΔG ttl ), namely, the ATP binding energy change upon a missense mutation in EGFR kinase domain, which can be calculated using a thermodynamic cycle scheme. [44] The ΔΔG mtt is expressed as the difference between the binding energies of ATP to wild-type kinase (ΔG ttl wt ) and to mutant kinase (ΔG ttl wt ), where only the ATP molecule and the mutated kinase residue were included in the high-level QM layer.…”

Section: Structural Modeling Of Atp Complexes With Wild-type and Mumentioning

confidence: 99%

Systematic characterization of adenosine triphosphate response to lung cancer epidermal growth factor receptor missense mutations: A molecular insight into “generic” drug resistance mutations

Wang

Yang

Liu

2020

J Chinese Chemical Soc

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Many missense mutations in human epidermal growth factor receptor (EGFR) are clinically involved in lung cancer and may cause acquired resistance to tyrosine kinase inhibitors. Traditionally, the resistance is considered to be established by impairing inhibitor affinity due to the mutations. However, it was found that, instead of blocking inhibitor binding, the gatekeeper mutation T790M can improve the kinase affinity for its natural substrate adenosine triphosphate (ATP), which is thus regarded as a "generic" resistance mutation that will reduce the potency of any ATP-competitive reversible kinase inhibitor. In this study, we attempt to systematically investigate the binding behavior of ATP to clinically observed EGFR missense mutants in nonsmall-cell lung cancer to identify those substantial mutations that may significantly increase (or decrease) ATP affinity. Several substantial mutations are excluded because they are also involved in kinase's catalytic activity or directly influence inhibitor binding, thus largely complicating the multiple dependent relationships of kinase, ATP, and inhibitor. Two new "generic" resistance mutations, A839T and E758G, are identified, which can improve ATP affinity by forming a favor

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Self-binding peptides: Binding-upon-folding versus folding-upon-binding

Cited by 68 publications

References 39 publications

Exploring the systematic effect of N‐substituted PxxP motifs on peptoid affinity to ARHGEF5/TIM SH3 domain and its relationship with ARHGEF5/TIM activation

Exploring the systematic effect of N‐substituted PxxP motifs on peptoid affinity to ARHGEF5/TIM SH3 domain and its relationship with ARHGEF5/TIM activation

Systematic response of staurosporine scaffold‐based inhibitors to drug‐resistant cancer kinase mutations

Systematic characterization of adenosine triphosphate response to lung cancer epidermal growth factor receptor missense mutations: A molecular insight into “generic” drug resistance mutations

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