7ubo

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Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor CCD-956

Structural highlights

7ubo is a 4 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 1.82Å
Ligands:DMS, MJN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BRDT_HUMAN Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis. Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time. In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA. Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids. Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin.[1] [2] [3]

Publication Abstract from PubMed

SignificanceBET bromodomain inhibition is therapeutic in multiple diseases; however, pan-BET inhibitors have induced significant myelosuppression and gastrointestinal toxicity, perhaps due to inhibition of both tandem bromodomains (BD) of all BET family members. However, selective inhibition of just the first BD (BD1) phenocopies pan-BET inhibitor activity in preclinical models of cancer, other diseases, and, for BRDT, in the testes for a contraceptive effect. Here, we leveraged our multibillion-molecule collection of DNA-encoded chemical libraries (DECLs) to identify BET BD1-selective inhibitors of specific chirality with high potency, stability, and good cellular activity. Our findings highlight the robustness and efficiency of the DECL platform to identify specific, potent protein binders that have promise as potential anticancer and anti-inflammatory agents and as male contraceptives.

Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.,Modukuri RK, Yu Z, Tan Z, Ta HM, Ucisik MN, Jin Z, Anglin JL, Sharma KL, Nyshadham P, Li F, Riehle K, Faver JC, Duong K, Nagarajan S, Simmons N, Palmer SS, Teng M, Young DW, Yi JS, Kim C, Matzuk MM Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2122506119. doi:, 10.1073/pnas.2122506119. Epub 2022 May 27. PMID:35622893[4]

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

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Citations
1 reviews cite this structure
Recent progress and structural analyses of domain-selective BET inhibitors.
Divakaran et al. (2023)
0 more
4 other articles
No citations found

References

  1. ↑ Jones MH, Numata M, Shimane M. Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics. 1997 Nov 1;45(3):529-34. PMID:9367677 doi:S0888-7543(97)95000-X
  2. ↑ Zheng Y, Yuan W, Zhou Z, Xu M, Sha JH. Molecular cloning and expression of a novel alternative splice variant of BRDT gene. Int J Mol Med. 2005 Feb;15(2):315-21. PMID:15647849
  3. ↑ Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE. Small-Molecule Inhibition of BRDT for Male Contraception. Cell. 2012 Aug 17;150(4):673-684. PMID:22901802 doi:10.1016/j.cell.2012.06.045
  4. ↑ Modukuri RK, Yu Z, Tan Z, Ta HM, Ucisik MN, Jin Z, Anglin JL, Sharma KL, Nyshadham P, Li F, Riehle K, Faver JC, Duong K, Nagarajan S, Simmons N, Palmer SS, Teng M, Young DW, Yi JS, Kim C, Matzuk MM. Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections. Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2122506119. PMID:35622893 doi:10.1073/pnas.2122506119

Contents


PDB ID 7ubo

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OCA

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