Targeting intrinsically disordered proteins at the edge of chaos

Ruan, Hao; Sun, Qi; Zhang, Weilin; Liu, Ying; Lai, Luhua

doi:10.1016/j.drudis.2018.09.017

Cited by 111 publications

(89 citation statements)

References 84 publications

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“…On the basis of our previous observation that TFP binds to NUPR1 and blocks its activity (29), leading to an anticancer effect in PDAC, we built models of the NUPR1-TFP complex, which could give us hints on how to improve the interaction with some novel derivatives. This constitutes an original ligand-based approach to the rational design of drugs against a totally unstructured protein, whereas previous pioneer attempts only included structure-based design against partly folded IDPs (40). The capacity of such new compounds to interact with NUPR1 was biophysically and biochemically validated using several spectroscopic and biophysical strategies.…”

Section: Discussionmentioning

confidence: 99%

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Santofimia‐Castaño¹,

Xia²,

Lan³

et al. 2019

Journal of Clinical Investigation

102

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Section: Discussionmentioning

confidence: 99%

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Santofimia‐Castaño¹,

Xia²,

Lan³

et al. 2019

Journal of Clinical Investigation

102

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“…The N-terminal and Ala/Pro-rich middle domains are considerably more diverse in sequence among characterized BCCP proteins. However, although diverse in sequence, the middle domain is rich in Ala and Pro residues, which is a common feature of BCCPs and of intrinsically disordered proteins (Uversky, 2016;Ruan et al, 2019).…”

Section: Badc3 Facilitates the Formation Of Bc-bccp Complexesmentioning

confidence: 99%

“…This latter middle domain is rich in Pro and Ala residues, and structural studies of homologous BCCP proteins indicate this domain is unstructured in solution. These are features common to intrinsically disordered proteins, which act as flexible linkers, facilitating the stabilization of transient complexes (Uversky, 2016;Ruan et al, 2019). In contrast, the C-terminal domain of BCCP, which carries the biotin prosthetic group, takes a distinct stable globular fold whose structure can be determined by NMR and x-ray crystallographic methods (Athappilly and Hendrickson, 1995;Yao et al, 1997;Roberts et al, 1999;Reddy et al, 2000).…”

Section: The Role Of Badc Paralogs In Bc-bccp Subcomplex Formation Anmentioning

confidence: 99%

Non-Catalytic Subunits Facilitate Quaternary Organization of Plastidic Acetyl-CoA Carboxylase

et al. 2019

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Arabidopsis (Arabidopsis thaliana), like most dicotyledonous plants, expresses a multicomponent, heteromeric acetyl-CoA carboxylase (htACCase), which catalyzes the generation of the malonyl-CoA precursor of de novo fatty acid biosynthesis. This enzyme consists of four catalytic subunits: biotin carboxylase (BC), carboxyltransferase (CT)-a, CT-b, and biotin carboxyl carrier protein (BCCP1 or BCCP2). By coexpressing combinations of components in a bacterial expression system, we demonstrate noncatalytic BADCs facilitate the assembly and activation of BCCP-BADC-BC subcomplexes catalyzing the bicarbonate-dependent hydrolysis of ATP, which is the first half-reaction catalyzed by the htACCase enzyme. Although BADC proteins do not directly impact formation of the CT-ab subcomplex, the BADC-facilitated BCCP-BADC-BC subcomplex can more readily interact with the CT-ab subcomplex to facilitate the generation of malonyl-CoA. The Arabidopsis genome encodes three BADC isoforms (BADC1, BADC2, and BADC3), and BADC2 and BADC3 (rather than BADC1), in combination with BCCP1, best support this quaternary-structural organization and catalytic activation of the htACCase enzyme. Physiological genetic studies validate these attributes as Arabidopsis double mutants singularly expressing BADC2, BADC3, or BADC1 present increasingly greater deleterious impacts on morphological and biochemical phenotypes. Specifically, plants expressing only BADC2 develop normally, plants only expressing BADC3 suffer a stunted root-growth phenotype, and plants expressing only BADC1 are embryo-lethal. The latter phenotype may also be associated with the distinct suborganelle localization of BADC1 in plastids as compared to the localization of the other two BADC homologs. These finding can inspire novel strategies to improve the biological sources of fats and oils for dietary and industrial applications.

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“…Our work and examples from other laboratories indicate that targeting of IDPs is feasible (even in proteins not involved in cancer development [103]). In all cases described so far, the molecules work by hampering the DNA-protein or protein-protein interactions in which the IDP is implicated.…”

Section: Discussionmentioning

confidence: 60%

Targeting intrinsically disordered proteins involved in cancer

Santofimia‐Castaño¹,

Rizzuti²,

Xia³

et al. 2019

Cell. Mol. Life Sci.

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Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in attractive therapeutic targets; however, targeting IDPs is challenging because of their dynamic nature. In the last years, different experimental and computational approaches, as well as the combination of both, have been explored to identify molecules to target either the hot-spots or the allosteric sites of IDPs. In this review, we summarize recent developments in successful targeting of IDPs, all of which are involved in different cancer types. The strategies used to develop and design (or in one particular example, to repurpose) small molecules targeting IDPs are, in a global sense, similar to those used in well-folded proteins: (1) screening of chemically diverse or target-oriented compound libraries; or (2) study of the interfaces involved in recognition of their natural partners, and design of molecular candidates capable of binding to such binding interface. We describe the outcomes of using these approaches in targeting IDPs involved in cancer, in the view to providing insight, to target IDPs in general. In a broad sense, the designed small molecules seem to target the most hydrophobic regions of the IDPs, hampering macromolecule (DNA or protein)-IDP interactions; furthermore, in most of the molecule-IDP complexes described so far, the protein remains disordered.

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Targeting intrinsically disordered proteins at the edge of chaos

Cited by 111 publications

References 84 publications

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Non-Catalytic Subunits Facilitate Quaternary Organization of Plastidic Acetyl-CoA Carboxylase

Targeting intrinsically disordered proteins involved in cancer

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