Sandbox Reserved 897

This Sandbox is Reserved from Jan 13 through July 31, 2020 for use in the course Protein Structure in Drug Discovery taught by Karen C. Glass at the ACPHS, Colchester, United States. This reservation includes Sandbox Reserved 895 through Sandbox Reserved 901.

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BRPF3 PWWP binding domain 3PFS

spinqualitylabelsall models BRPF3 PWWP domain Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Overview The PWWP domain belongs to the Royal family, which consists of Tudor, chromodomain, MBT(Malignant Brain Tumor), and PWWP domains. The PWWP domain was first identified as a structural motif includes 100 to 130 amino acids in WHSC1 protein research. The researchers named after its very conservative sequence, Pro-Trp-Trp-Pro located at the β2 strand of protein. This domain is mainly related to the recognition of methylated histone tail lysine and related to the epigenetic regulation of genes. Bromodomain and PHD finger-containing protein family is the group of proteins found in higher eukaryotes. The members have similar structural features and affinity to genes. Unlike BRPF1 and 2, BRPF3 is less studied by the researchers. Therefore many of its function remains unknown. BRPF1 PWWP domain, which has very similar structure with 3pfs, presents on actively transcribing cells and may regulate Hox A9 gene which is related to MOZ-TIF2-dependant leukemia. The 3pfs motif is relatively mystery we may assume that 3pfs also do similar works Structure The main characteristic of PWWP domains is the two distinctive substructural motifs: β-barrel at the N-terminal region and helixes at C-terminal region. The β-barrel is a very conservative feature of PWWP domains and the one at 3pfs is composed of 5 β-strands. The helixes at the C-terminal region are very different and 3pfs has 3 helixes which are little more than many of its relatives. The Pro-Trp-Trp-Pro motif, which is the most conservative, is little different in 3pfs, just like its closely-related proteins. The PWWP domains in BRPF family are composed of Tyr-Pro-Ser-Tyr and may suggest they would have a similar affinity. The stability of domain comes from both inter-substructure and intra-substructure interactions including hydrogen bonds and polar interactions. One unique feature of PWWP motif is that the first position affects the stability and aggregation of the protein. The proline gives more stability and oligomerization to the protein, compared to the alanine at the same position. Figure 1: Cartoon model of 3PFS motif. β-sheets(magenta) and helixes(orange) are shown. generated in PyMOL using PDB: 3PFS Function Methyl-lysine reader PWWP domains are one of epigenetic regulators which recognize specific lysine residues which are methylated. Even though there is no detailed research on 3pfs, it may be assumed to have similar function with BRPF1 PWWP domain which is shown to have methylated histone binding activity. With a high-throughput mass spectrometry screening, this motif is suggested as an essential motif of histone 3 lysine 36 trimethylation binding. The β-strands and Pro-Trp-Trp-Pro motif form hydrophobic cavity, which is the binding site of methylated lysines. Since the aromatic cage is a common structure in the Royal family, it can be a common tool for methylated lysine binding. Nonspecific binding The PWWP domains have a significant amount of basic residues which gives ability of nonspecific binding on DNA strands. BRPF3 3pfs protein has 11 lysine residues and 12 arginine residues. These residues' sidechains remain being positively charged on in vivo pH. The DNA strand phosphate backbone, which is negatively charged, would be attracted to PWWP domain surface due to the nature of attraction between the opposite charges. Figure 2: Lysine(yellow) and Arginine(red) residues on 3PFS surface interacting with DNA backbone generated in PyMOL using PDB: 3PFS Evolutionary conservations PWWP domain is only found in eukaryotes, from a yeast to a human. The number of PWWP containing protein is also varying on species; the human has 20. The loyal family has a common structural characteristic, three conserved β-strands. The PWWP domain is also believed to be evolved from a common ancestor which had 3 β-strands. The most conservative section is the PWWP sequence, which it is named after. Therapheutic features There is no research on the relationship between BRPF3 PWWP domain and any human disease. However, both of its closely related domains BRPF1 and BRPF2 PWWP domains are associated with hox gene regulation, that is associated with schizophrenia and bipolar affective disorder. Therefore BRPF3 PWWP domain, which has very similar β-barrel structure with previous proteins, may also have Hox gene-related function. But a further research would be required. This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.