8bdn

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VCB in complex with compound 23

Structural highlights

8bdn is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.76Å
Ligands:CAS, QFR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ELOB_HUMAN SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).[1] [2] The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.[3] [4]

Publication Abstract from PubMed

Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for the first time a consistent data set which allows for direct comparison of structural variations including those which were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design a small library of highly potent BRD4-degraders comprising different VHL exit vectors. Newly designed degraders showed favorable molecular properties and significantly improved degradation potency compared to MZ1.

Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design.,Krieger J, Sorrell FJ, Wegener AA, Leuthner B, Machrouhi-Porcher F, Hecht M, Leibrock EM, Muller JE, Eisert J, Hartung IV, Schlesiger S ChemMedChem. 2023 Apr 17;18(8):e202200615. doi: 10.1002/cmdc.202200615. Epub 2023 , Feb 28. PMID:36749883[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
0 reviews cite this structure
DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.
Schröder et al. (2024)
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5 other articles
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References

  1. ↑ Garrett KP, Aso T, Bradsher JN, Foundling SI, Lane WS, Conaway RC, Conaway JW. Positive regulation of general transcription factor SIII by a tailed ubiquitin homolog. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7172-6. PMID:7638163
  2. ↑ Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, Rechavi G, Yarden Y. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005 Feb 25;280(8):7038-48. Epub 2004 Dec 7. PMID:15590694 doi:10.1074/jbc.M408575200
  3. ↑ Garrett KP, Aso T, Bradsher JN, Foundling SI, Lane WS, Conaway RC, Conaway JW. Positive regulation of general transcription factor SIII by a tailed ubiquitin homolog. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7172-6. PMID:7638163
  4. ↑ Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, Rechavi G, Yarden Y. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005 Feb 25;280(8):7038-48. Epub 2004 Dec 7. PMID:15590694 doi:10.1074/jbc.M408575200
  5. ↑ Krieger J, Sorrell FJ, Wegener AA, Leuthner B, Machrouhi-Porcher F, Hecht M, Leibrock EM, Müller JE, Eisert J, Hartung IV, Schlesiger S. Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design. ChemMedChem. 2023 Feb 7:e202200615. PMID:36749883 doi:10.1002/cmdc.202200615

Contents


PDB ID 8bdn

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OCA

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