Bromodomain

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Bromodomain
SCOP2
1b91 / SCOPe / SUPFAM
CDDcd04369
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1e6i​, 1eqf​, 1f68​, 1jm4​, 1jsp​, 1n72​, 1wug​, 1wum​, 1zs5​, 2d82​

A bromodomain is an approximately 110 amino acid

all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.[1][3]

Discovery

The bromodomain was identified as a novel

Brahma/brm, and showed sequence similarity to genes involved in transcriptional activation.[4] The name "bromodomain" is derived from the relationship of this domain with Brahma and is unrelated to the chemical element bromine
.

Bromodomain-containing proteins

Bromodomain-containing proteins can have a wide variety of functions, ranging from histone acetyltransferase activity and chromatin remodeling to transcriptional mediation and co-activation. Of the 43 known in 2015, 11 had two bromodomains, and one protein had 6 bromodomains.[2] Preparation, biochemical analysis, and structure determination of the bromodomain containing proteins have been described in detail.[5]

Bromo- and Extra-Terminal domain (BET) family

A well-known example of a bromodomain family is the BET (Bromodomain and extraterminal domain) family. Members of this family include

BRD3, BRD4 and BRDT.[6]

Other

However proteins such as

Histone acetyltransferases, including EP300 and PCAF, have bromodomains in addition to acetyl-transferase domains.[8][9][10]

Not considered part of the BET family (yet containing a bromodomain) are BRD7, and BRD9.

Role in human disease

The role of bromodomains in translating a deregulated cell acetylome into disease phenotypes was recently unveiled by the development of small molecule bromodomain inhibitors. This breakthrough discovery highlighted bromodomain-containing proteins as key players in cancer biology, as well as inflammation[11] and remyelination in multiple sclerosis.[2]

Members of the BET family have been implicated as targets in both human cancer

BET inhibitors have shown therapeutic effects in multiple preclinical models of cancer and are currently in clinical trials in the United States.[15]
Their application in multiple sclerosis is still in the preclinical stage.

Small molecule inhibitors of non-BET bromodomain proteins BRD7 and BRD9 have also been developed.[16][17]

See also

References

  1. ^
    PMID 11080160
    .
  2. ^
    PMID 26472704
    .
  3. S2CID 29706103
    .
  4. S2CID 27726226
    .
  5. PMID 27372760
    .
  6. PMID 27827996
    .
  7. PMID 22464331
    .
  8. S2CID 1210925
    .
  9. PMID 17047066
    .
  10. PMID 24946055
    .
  11. PMID 33462181
    .
  12. PMID 26077433
    .
  13. PMID 23872705
    .
  14. PMID 24954007
    .
  15. PMID 24905006
    .
  16. PMID 25864491
    .
  17. PMID 25856009
    .
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