Rational drug design via intrinsically disordered protein

Cheng, Yugong; LeGall, Tanguy; Oldfield, Christopher J.; Mueller, J; Van, Ya Yue J.; Romero, Pedro; Cortese, Marc S.; Uversky, Vladimir N.; Dunker, A. Keith

doi:10.1016/j.tibtech.2006.07.005

Cited by 231 publications

(200 citation statements)

References 49 publications

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“…Given their importance, many human disease-associated proteins related to cancer, diabetes, autoimmune disease, neurodegenerative disease, and cardiovascular disease are found to have predicted disordered binding regions (MoRFs) as we expect. 87 These MoRFs associate with other structured partners and considered as promising druggable interactions because of their high specificity and low affinity for binding. Binding with relatively low affinity is an advantageous attribute for transient, conditional, and tunable interactions, which is needed for many regulatory events.…”

Section: Discussionmentioning

confidence: 99%

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

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Section: Discussionmentioning

confidence: 99%

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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“…It remains to be determined what other partners exist for HdmX. Our observations, therefore, provide the molecular basis to better understand and predict the interactions of HdmX with its potentially diverse biological targets (35,37), which should ultimately lead to a better understanding of the biological roles of HdmX.…”

Section: A Chlorine Substituent At the Bottom Of The Trp Pocket Of Hdmentioning

confidence: 93%

“…Third, the observed conformational changes of HdmX when bound to various ligands suggests that our previous view of HdmX being a rigid structure to which the disordered p53 peptide binds is limited. In this sense, low molecular mass antagonists would be expected to not only have lower required binding energy (37) but could also bind to HdmX in a manner that may mimic an induced fit (38). This would suggest the association rate for these compounds to be low.…”

Section: A Chlorine Substituent At the Bottom Of The Trp Pocket Of Hdmentioning

confidence: 99%

Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes

Kallen

Goepfert

Blechschmidt

et al. 2009

Journal of Biological Chemistry

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“…A complex example where dynamics is crucial is constituted by Intrinsically Disordered Proteins (IDPs) [9,10]. For these proteins, their dynamic nature plays an essential role due to fundamentally exist as conformational ensembles.…”

Section: The Challenge Of Targeting Intrinsically Disordered Proteinsmentioning

confidence: 99%

“…For instance, the conformational flexibility of the N-terminal Huntingtin is responsible of the formation of transient helical structures to oligomerization [40,41]. Targeting the conformational variability, i.e., targeting the dynamics of IDPs is a potential therapeutic strategy and in that sense, IDPs and their binding partners [9,10,42] have been designed as targetable proteins.…”

Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

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2017

MOJPB

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Intrinsically disordered proteins (IDPs) are characterized by a lack of folded structure. Since their identification more than a decade ago, they were designed as potential drug targets. However, nowadays, only few therapeutic molecules have been designed against them. Due to the nature of these proteins bioinformatics methods could have a key role disentangling IDPs related issues, which is key to design new therapeutic agents against them.

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Rational drug design via intrinsically disordered protein

Cited by 231 publications

References 49 publications

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes

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