7l9a

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Crystal structure of BRDT bromodomain 2 in complex with CDD-1102

Structural highlights

7l9a is a 2 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 2.27Å
Ligands:BME, XWP
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

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined for their ability to compete with JQ1 in BRDT and BRD4 bromodomain AlphaScreen assays. These studies identified CDD-1102 as a selective BRDT-BD2 inhibitor with low nanomolar potency and >1,000-fold selectivity over BRDT-BD1. Structure-activity relationship studies of CDD-1102 produced a series of additional BRDT-BD2/BRD4-BD2 selective inhibitors, including CDD-1302, a truncated analog of CDD-1102 with similar activity, and CDD-1349, an analog with sixfold selectivity for BRDT-BD2 versus BRD4-BD2. BROMOscan bromodomain profiling confirmed the great affinity and selectivity of CDD-1102 and CDD-1302 on all BET BD2 versus BD1 with the highest affinity for BRDT-BD2. Cocrystals of BRDT-BD2 with CDD-1102 and CDD-1302 were determined at 2.27 and 1.90 A resolution, respectively, and revealed BRDT-BD2 specific contacts that explain the high affinity and selectivity of these compounds. These BD2-specific compounds and their binding to BRDT-BD2 are unique compared with recent reports and enable further evaluation of their nonhormonal contraceptive potential in vitro and in vivo.

Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.,Yu Z, Ku AF, Anglin JL, Sharma R, Ucisik MN, Faver JC, Li F, Nyshadham P, Simmons N, Sharma KL, Nagarajan S, Riehle K, Kaur G, Sankaran B, Storl-Desmond M, Palmer SS, Young DW, Kim C, Matzuk MM Proc Natl Acad Sci U S A. 2021 Mar 2;118(9). pii: 2021102118. doi:, 10.1073/pnas.2021102118. PMID:33637650[4]

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

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Citations
6 reviews cite this structure
Functional Roles of Bromodomain Proteins in Cancer.
Boyson et al. (2021)
5 more
13 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. ↑ Yu Z, Ku AF, Anglin JL, Sharma R, Ucisik MN, Faver JC, Li F, Nyshadham P, Simmons N, Sharma KL, Nagarajan S, Riehle K, Kaur G, Sankaran B, Storl-Desmond M, Palmer SS, Young DW, Kim C, Matzuk MM. Discovery and characterization of bromodomain 2-specific inhibitors of BRDT. Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):e2021102118. PMID:33637650 doi:10.1073/pnas.2021102118

Contents


PDB ID 7l9a

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