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Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation.

Bulatov E, Ciulli A - Biochem. J. (2015)

Bottom Line: In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity.A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included.This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

View Article: PubMed Central - PubMed

Affiliation: *College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.

ABSTRACT
In the last decade, the ubiquitin-proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin-RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

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Assembly between adaptor subunits and Cullins(A) Skp1–Cul1 (PDB code 1LDK). (B) BTB protein KLHL3–Cul3 (PDB code 4HXI). (C) ElonginC–Cul5 (PDB code 4JGH). The adaptor proteins bind the N-terminal surface of their respective Cullins to form extended and predominantly hydrophobic interfaces.
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Figure 3: Assembly between adaptor subunits and Cullins(A) Skp1–Cul1 (PDB code 1LDK). (B) BTB protein KLHL3–Cul3 (PDB code 4HXI). (C) ElonginC–Cul5 (PDB code 4JGH). The adaptor proteins bind the N-terminal surface of their respective Cullins to form extended and predominantly hydrophobic interfaces.

Mentions: The general CRL architecture varies depending on the family member. Remarkably, CRL3 utilizes substrate-specific adaptors that implement a dual adaptor/receptor function within a single polypeptide chain [22,58–60]. These proteins usually contain several domains and are characterized by a common structural motif called the BTB fold that binds the N-terminal end of the Cul3 scaffold. The human genome encodes over 200 BTB proteins [22] that were originally discovered in the bric-a-brac, tramtrack and broad complex transcription factors of Drosophila melanogaster [61]. Importantly, comparison with other CRLs shows that BTB–Cul3, ElonginC–Cul2/5 and Skp1–Cul1 interfaces are structurally analogous to each other, although the interacting subunits are not interchangeable [59] (Figure 3).


Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation.

Bulatov E, Ciulli A - Biochem. J. (2015)

Assembly between adaptor subunits and Cullins(A) Skp1–Cul1 (PDB code 1LDK). (B) BTB protein KLHL3–Cul3 (PDB code 4HXI). (C) ElonginC–Cul5 (PDB code 4JGH). The adaptor proteins bind the N-terminal surface of their respective Cullins to form extended and predominantly hydrophobic interfaces.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403949&req=5

Figure 3: Assembly between adaptor subunits and Cullins(A) Skp1–Cul1 (PDB code 1LDK). (B) BTB protein KLHL3–Cul3 (PDB code 4HXI). (C) ElonginC–Cul5 (PDB code 4JGH). The adaptor proteins bind the N-terminal surface of their respective Cullins to form extended and predominantly hydrophobic interfaces.
Mentions: The general CRL architecture varies depending on the family member. Remarkably, CRL3 utilizes substrate-specific adaptors that implement a dual adaptor/receptor function within a single polypeptide chain [22,58–60]. These proteins usually contain several domains and are characterized by a common structural motif called the BTB fold that binds the N-terminal end of the Cul3 scaffold. The human genome encodes over 200 BTB proteins [22] that were originally discovered in the bric-a-brac, tramtrack and broad complex transcription factors of Drosophila melanogaster [61]. Importantly, comparison with other CRLs shows that BTB–Cul3, ElonginC–Cul2/5 and Skp1–Cul1 interfaces are structurally analogous to each other, although the interacting subunits are not interchangeable [59] (Figure 3).

Bottom Line: In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity.A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included.This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

View Article: PubMed Central - PubMed

Affiliation: *College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.

ABSTRACT
In the last decade, the ubiquitin-proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin-RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

Show MeSH
Related in: MedlinePlus