Sandbox Reserved 896: Difference between revisions

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{{Sandbox_reserved_Karen_Glass_2020}}

==Structural and Functional Overview of Human BRD2 ~~BD1 Bromodomain~~==

==Structural and Functional Overview of Human BRD2 (RING3) Protein==

==General Overview==

Human bromodomain-containing protein 2 (BRD2) is a highly conserved and ubiquitously expressed protein involved in transcriptional regulation and recognition of post-translational histone modifications. BRD2 is a bromodomain and extra-terminal domain (BET) family protein, which are characterized by the presence of two adjacent bromodomains as well as an extra-terminal domain. Bromodomain and extra terminal domain (BET) family proteins are a group of related proteins involved in the specific recognition of acetylated lysine residues on chromatin and subsequent transcriptional activation [2]. As a BET protein, BRD2 follows this structural motif with its structure consisting of ~~bromodomain 1 (BRD2-BD1)~~ at the N-terminus, bromodomain 2 (BRD2-BD2), and ~~an N~~-~~extra~~-~~terminal (NET) domain~~. Human BRD2 is encoded by the gene BRD2, which consists of 11 exons that cover more than 6 kb of genomic DNA [1]. This gene was formerly known as really interesting new gene 3 (RING3) but was later renamed to BRD2.

Human bromodomain-containing protein 2 (BRD2) is a highly conserved and ubiquitously expressed protein involved in transcriptional regulation and recognition of post-translational histone modifications. BRD2 is a bromodomain and extra-terminal domain (BET) family protein, which are characterized by the presence of two adjacent bromodomains as well as an extra-terminal domain. Bromodomain and extra terminal domain (BET) family proteins are a group of related proteins involved in the specific recognition of acetylated lysine residues on chromatin and subsequent transcriptional activation [2]. As a BET protein, BRD2 follows this structural motif with its structure consisting of an NET domain at the N-terminus, followed by bromodomain 2 (BRD2-BD2), and finally bromodomain 1 (BRD2-BD1) at the C-terminus. Human BRD2 is encoded by the gene BRD2, which consists of 11 exons that cover more than 6 kb of genomic DNA [1]. This gene was formerly known as really interesting new gene 3 (RING3) but was later renamed to BRD2.

[[Media:BRDTry4.mp4]]

== Function ==

Human BRD2 protein is a Serine-Threonine kinase found ubiquitously amongst the nuclear envelope of ~~all cell~~ types. The activity of BRD2 is increased during cell proliferation. BRD2 specifically recognizes an N-acetyl-lysine residue at position 12 of histone H4 ~~via a homo-2-mer complex of BD1 domains~~. ~~The~~ BRD2-BD1 ~~domain recognizes the H4 tail only when lysine-12 is acetylated. This recognition is mediated through the binding of the hypoacetylated side chain of lysine at position 8 of H4~~ with ~~the interface~~ between ~~dimerized BRD2-BD1 domains [3]. BRD2 has also shown in vitro interaction with~~ N-acetyl-lysine at position 5 of H4, ~~but this interaction has not been shown to involve lysine-8 of H4~~ [3]. It is presumed that one of the functions of this recognition is to prevent deletion or erasure of post-translational histone markers during the mitotic cell cycle. The transcriptional regulation activity of BRD2 is also mediated through its positive regulation of E2F-dependent cell cycle progression (direct stimulation of E2F reporter activity) [1]. As E2F’s central function is to promote the synthesis of proteins needed for G1 to S transition, BRD2-BD1 is directly implicated in the regulation of the cell cycle.

Human BRD2 protein is a Serine-Threonine kinase and chromatin regulator found ubiquitously amongst the nuclear envelope of 223 tissue types. The activity of BRD2 is increased during cell proliferation. BRD2 specifically recognizes an N-acetyl-lysine residue at position 12 of histone H4 [3]. BRD2-BD1 and BD2 preferentially bind diacetylated peptides with optimal spacing between N-acetyl-lysine residues. BD1 has particular affinity for diacetylated lysine residues at position 5 and 8 of H4, whereas BD2 is significantly more promiscuous [6]. It is presumed that one of the functions of this recognition is to prevent deletion or erasure of post-translational histone markers during the mitotic cell cycle. The transcriptional regulation activity of BRD2 is also mediated through its positive regulation of E2F-dependent cell cycle progression (direct stimulation of E2F reporter activity) [1]. As E2F’s central function is to promote the synthesis of proteins needed for G1 to S transition, BRD2-BD1 is directly implicated in the regulation of the cell cycle. BRD2-BD1 also interacts with latency-associated nuclear antigen 1 (LANA-1), a protein involved in Kaposi’s sarcoma-associated herpesvirus [5]. BRD2-BD2 is known to facilitate recruitment of other BET proteins to induce gene expression in specific phases of the cell cycle [6].

[[Image:BRD2BD1SurfaceView.png]]

Figure 1: Surface view of BD1 ~~homo-2-mer~~ binding N-acetyl-lysine 12 of histone H4. The hypoacetylated side chain of lysine 8 that coordinates the dimer interface cannot be seen in this figure. Figure produced by PyMol (PDB ID: 2DVQ).

Figure 1: Surface view of BD1 binding N-acetyl-lysine 12 of histone H4. The hypoacetylated side chain of lysine 8 that coordinates the dimer interface cannot be seen in this figure. Figure produced by PyMol (PDB ID: 2DVQ) [17].

== Structure ==

Line 39:

[[Image:BD1HomodimerTertiaryStructure.png]]

Figure 2: Tertiary Structure of BRD2-BD1 ~~homodimer~~ in complex with N-acetyl-lysine 12 of histone H4. Figure produced by PyMol (PDB ID: 2DVQ)

Figure 2: Tertiary Structure of BRD2-BD1 in complex with N-acetyl-lysine 12 of histone H4. Figure produced by PyMol (PDB ID: 2DVQ) [17].

== Medical Relevance ==

Line 67:

'''Figure 3: BRD2-BD1 to BRD2-BD2 Alignment'''

[[Image:BD1BD2Alignment.png]]

Sequences derived from Uniprot. Figure produced by Clustal Omega [18].

Key: P25440 (91-163) = BRD2-BD1; P25440 (364-463) = BRD2-BD2; * = identical residue; . = chemically similar residue; : = very chemically similar residue

Sequence Identity: 39 / 73 = 53%

Sequence Similarity: (39 + 23) / 73 = 85%

'''As stated above, it is the low level of sequence identity shared between BRD2-BD1 and BRD2-BD2 that allows for selective drug targeting. The sequence identity is most divergent in the regions consisting the ZA and BC loops, with BD2 containing key residues of Leu383 and Asn429.'''

'''Figure 4: BD1 Alignment Among BET Proteins'''

Line 72:

Line 85:

[[Image:BD1Alignment.png]]

Sequences derived from Uniprot. Figure produced by Clustal Omega.

Sequences derived from Uniprot. Figure produced by Clustal Omega [18].

Key: P25440 = BRD2; Q15059 = BRD3; O60885 = BRD4; Q58F21 = BRDT; * = identical residue; . = chemically similar residue; : = very chemically similar residue.

Line 79:

Line 92:

Overall Sequence Similarity: (50 + 15) / 73 = 89%

'''Figure 5: BD2 Alignment Among BET Proteins'''

Line 84:

Line 98:

[[Image:BD2Alignment.png]]

Sequences derived from Uniprot. Figure produced by Clustal Omega

Sequences derived from Uniprot. Figure produced by Clustal Omega [18].

Key: P25440 = BRD2; Q15059 = BRD3; O60885 = BRD4; Q58F21 = BRDT; * = identical residue; . = chemically similar residue; : = very chemically similar residue.

Line 91:

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Overall Sequence Similarity: (47 + 17) / 73 = 88%

'''Figure 6: NET Alignment Among BET Proteins'''

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Line 111:

[[Image:NETAlignment.png]]

Sequences derived from Uniprot. Figure produced by Clustal Omega.

Sequences derived from Uniprot. Figure produced by Clustal Omega [18].

Key: P25440 = BRD2; Q15059 = BRD3; O60885 = BRD4; Q58F21 = BRDT; * = identical residue; . = chemically similar residue; : = very chemically similar residue.

Line 107:

Line 122:

== References ==

[1] Taniguchi Y. The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins. International Journal of Molecular Sciences. 2016Jul;17(11):1849.

[2] Nakamura Y, Umehara T, Nakano K, Jang MK, Shirouzu M, Morita S, et al. Crystal Structure of the Human BRD2 Bromodomain: INSIGHTS INTO DIMERIZATION AND RECOGNITION OF ACETYLATED HISTONE H4. Journal of Biological Chemistry. 2006;282(6):4193–201.

[3] Umehara T, Nakamura Y, Jang MK, Nakano K, Tanaka A, Ozato K, et al. Structural Basis for Acetylated Histone H4 Recognition by the Human BRD2 Bromodomain. Journal of Biological Chemistry. 2010Apr;285(10):7610–8.

[4] Wang Q, Li Y, Xu J, Wang Y, Leung EL-H, Liu L, et al. Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations. Scientific Reports. 2017;7(1).

[5] Viejo-Borbolla A, Ottinger M, Bruning E, Burger A, Konig R, Kati E, et al. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's Sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. Journal of Virology. 2005Nov;

[6] Gilan O, Rioja I, Knezevic K, Bell M, Yeung M. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020Apr24;368(6489):387–94.

[7] Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. BRD2 (RING3) Is a Probable Major Susceptibility Gene for Common Juvenile Myoclonic Epilepsy. The American Journal of Human Genetics. 2003;73(2):261–70.

[8] UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain-containing protein 2 [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/P25440#expression

[9] UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain-containing protein 3 [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/Q15059

[10] UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain-containing protein 4 [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/O60885

[11] UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain testis-specific protein [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/Q58F21

[12] RCSB Protein Data Bank. 2DVQ: Crystal structure analysis of the N-terminal bromodomain of human BRD2 complexed with acetylated histone H4 peptide [Internet]. RCSB PDB. [cited 2020Apr28]. Available from: https://www.rcsb.org/structure/2DVQ

[13] Tommaso PD, Moretti S, Xenarios I, Orobitg M, Montanyola A, Chang J-M, et al. T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension. Nucleic Acids Research. 2011Sep;39(suppl).

[14] Armougom F, Moretti S, Poirot O, Audic S, Dumas P, Schaeli B, et al. Expresso: automatic incorporation of structural information in multiple sequence alignments using 3D-Coffee. Nucleic Acids Research. 2006Jan;34(Web Server).

[15] Osullivan O. 3DCoffee: Combining Protein Sequences and Structures within Multiple Sequence Alignments. Journal of Molecular Biology. 2004;

[16] Notredame C, Higgins DG, Heringa J. T-coffee: a novel method for fast and accurate multiple sequence alignment. Thornton J, editor. Journal of Molecular Biology. 2000;302(1):205–17.

[17] The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.

[18] 18. Sievers F, Higgins DG. Clustal Omega, Accurate Alignment of Very Large Numbers of Sequences. Methods in Molecular Biology Multiple Sequence Alignment Methods. 2013;:105–16.

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@@ Line 1: / Line 1: @@
 {{Sandbox_reserved_Karen_Glass_2020}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
-==Structural and Functional Overview of Human BRD2 BD1 Bromodomain==
+==Structural and Functional Overview of Human BRD2 (RING3) Protein==
-<Structure load='2DVQ' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
+<Structure load='2DVQ' size='350' frame='true' align='right' caption='BD1 homo-2-mer coordination of N-acetyl-lysine 12 of histone H4' scene='Insert optional scene name here' />
 ==General Overview==
-Human bromodomain-containing protein 2 (BRD2) is a highly conserved and ubiquitously expressed protein involved in transcriptional regulation and recognition of post-translational histone modifications. BRD2 is a bromodomain and extra-terminal domain (BET) family protein, which are characterized by the presence of two adjacent bromodomains as well as an extra-terminal domain. Bromodomain and extra terminal domain (BET) family proteins are a group of related proteins involved in the specific recognition of acetylated lysine residues on chromatin and subsequent transcriptional activation [2]. As a BET protein, BRD2 follows this structural motif with its structure consisting of bromodomain 1 (BRD2-BD1) at the N-terminus, bromodomain 2 (BRD2-BD2), and an N-extra-terminal (NET) domain. Human BRD2 is encoded by the gene BRD2, which consists of 11 exons that cover more than 6 kb of genomic DNA [1]. This gene was formerly known as really interesting new gene 3 (RING3) but was later renamed to BRD2.
+Human bromodomain-containing protein 2 (BRD2) is a highly conserved and ubiquitously expressed protein involved in transcriptional regulation and recognition of post-translational histone modifications. BRD2 is a bromodomain and extra-terminal domain (BET) family protein, which are characterized by the presence of two adjacent bromodomains as well as an extra-terminal domain. Bromodomain and extra terminal domain (BET) family proteins are a group of related proteins involved in the specific recognition of acetylated lysine residues on chromatin and subsequent transcriptional activation [2]. As a BET protein, BRD2 follows this structural motif with its structure consisting of an NET domain at the N-terminus, followed by bromodomain 2 (BRD2-BD2), and finally bromodomain 1 (BRD2-BD1) at the C-terminus. Human BRD2 is encoded by the gene BRD2, which consists of 11 exons that cover more than 6 kb of genomic DNA [1]. This gene was formerly known as really interesting new gene 3 (RING3) but was later renamed to BRD2.
 [[Media:BRDTry4.mp4]]
 == Function ==
-Human BRD2 protein is a Serine-Threonine kinase found ubiquitously amongst the nuclear envelope of all cell types. The activity of BRD2 is increased during cell proliferation. BRD2 specifically recognizes an N-acetyl-lysine residue at position 12 of histone H4 via a homo-2-mer complex of BD1 domains. The BRD2-BD1 domain recognizes the H4 tail only when lysine-12 is acetylated. This recognition is mediated through the binding of the hypoacetylated side chain of lysine at position 8 of H4 with the interface between dimerized BRD2-BD1 domains [3]. BRD2 has also shown in vitro interaction with N-acetyl-lysine at position 5 of H4, but this interaction has not been shown to involve lysine-8 of H4 [3]. It is presumed that one of the functions of this recognition is to prevent deletion or erasure of post-translational histone markers during the mitotic cell cycle. The transcriptional regulation activity of BRD2 is also mediated through its positive regulation of E2F-dependent cell cycle progression (direct stimulation of E2F reporter activity) [1]. As E2F’s central function is to promote the synthesis of proteins needed for G1 to S transition, BRD2-BD1 is directly implicated in the regulation of the cell cycle.
+Human BRD2 protein is a Serine-Threonine kinase and chromatin regulator found ubiquitously amongst the nuclear envelope of 223 tissue types. The activity of BRD2 is increased during cell proliferation. BRD2 specifically recognizes an N-acetyl-lysine residue at position 12 of histone H4 [3]. BRD2-BD1 and BD2 preferentially bind diacetylated peptides with optimal spacing between N-acetyl-lysine residues. BD1 has particular affinity for diacetylated lysine residues at position 5 and 8 of H4, whereas BD2 is significantly more promiscuous [6]. It is presumed that one of the functions of this recognition is to prevent deletion or erasure of post-translational histone markers during the mitotic cell cycle. The transcriptional regulation activity of BRD2 is also mediated through its positive regulation of E2F-dependent cell cycle progression (direct stimulation of E2F reporter activity) [1]. As E2F’s central function is to promote the synthesis of proteins needed for G1 to S transition, BRD2-BD1 is directly implicated in the regulation of the cell cycle. BRD2-BD1 also interacts with latency-associated nuclear antigen 1 (LANA-1), a protein involved in Kaposi’s sarcoma-associated herpesvirus [5]. BRD2-BD2 is known to facilitate recruitment of other BET proteins to induce gene expression in specific phases of the cell cycle [6].
 [[Image:BRD2BD1SurfaceView.png]]
-Figure 1: Surface view of BD1 homo-2-mer binding N-acetyl-lysine 12 of histone H4. The hypoacetylated side chain of lysine 8 that coordinates the dimer interface cannot be seen in this figure. Figure produced by PyMol (PDB ID: 2DVQ).
+Figure 1: Surface view of BD1 binding N-acetyl-lysine 12 of histone H4. The hypoacetylated side chain of lysine 8 that coordinates the dimer interface cannot be seen in this figure. Figure produced by PyMol (PDB ID: 2DVQ) [17].
 == Structure ==
@@ Line 39: / Line 39: @@
 [[Image:BD1HomodimerTertiaryStructure.png]]
-Figure 2: Tertiary Structure of BRD2-BD1 homodimer in complex with N-acetyl-lysine 12 of histone H4. Figure produced by PyMol (PDB ID: 2DVQ)
+Figure 2: Tertiary Structure of BRD2-BD1 in complex with N-acetyl-lysine 12 of histone H4. Figure produced by PyMol (PDB ID: 2DVQ) [17].
 == Medical Relevance ==
@@ Line 67: / Line 67: @@
 '''Figure 3: BRD2-BD1 to BRD2-BD2 Alignment'''
+[[Image:BD1BD2Alignment.png]]
+Sequences derived from Uniprot. Figure produced by Clustal Omega [18].
+Key: P25440 (91-163) = BRD2-BD1; P25440 (364-463) = BRD2-BD2; * = identical residue; . = chemically similar residue; : = very chemically similar residue
+Sequence Identity: 39 / 73 = 53%
+Sequence Similarity: (39 + 23) / 73 = 85%
+'''As stated above, it is the low level of sequence identity shared between BRD2-BD1 and BRD2-BD2 that allows for selective drug targeting. The sequence identity is most divergent in the regions consisting the ZA and BC loops, with BD2 containing key residues of Leu383 and Asn429.'''
 '''Figure 4: BD1 Alignment Among BET Proteins'''
@@ Line 72: / Line 85: @@
 [[Image:BD1Alignment.png]]
-Sequences derived from Uniprot. Figure produced by Clustal Omega.
+Sequences derived from Uniprot. Figure produced by Clustal Omega [18].
 Key: P25440 = BRD2; Q15059 = BRD3; O60885 = BRD4; Q58F21 = BRDT; * = identical residue; . = chemically similar residue; : = very chemically similar residue.
@@ Line 79: / Line 92: @@
 Overall Sequence Similarity: (50 + 15) / 73 = 89%
 '''Figure 5: BD2 Alignment Among BET Proteins'''
@@ Line 84: / Line 98: @@
 [[Image:BD2Alignment.png]]
-Sequences derived from Uniprot. Figure produced by Clustal Omega
+Sequences derived from Uniprot. Figure produced by Clustal Omega [18].
 Key: P25440 = BRD2; Q15059 = BRD3; O60885 = BRD4; Q58F21 = BRDT; * = identical residue; . = chemically similar residue; : = very chemically similar residue.
@@ Line 91: / Line 105: @@
 Overall Sequence Similarity: (47 + 17) / 73 = 88%
 '''Figure 6: NET Alignment Among BET Proteins'''
@@ Line 96: / Line 111: @@
 [[Image:NETAlignment.png]]
-Sequences derived from Uniprot. Figure produced by Clustal Omega.
+Sequences derived from Uniprot. Figure produced by Clustal Omega [18].
 Key: P25440 = BRD2; Q15059 = BRD3; O60885 = BRD4; Q58F21 = BRDT; * = identical residue; . = chemically similar residue; : = very chemically similar residue.
@@ Line 107: / Line 122: @@
 == References ==
+[1]	Taniguchi Y. The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins. International Journal of Molecular Sciences. 2016Jul;17(11):1849.
+[2]	Nakamura Y, Umehara T, Nakano K, Jang MK, Shirouzu M, Morita S, et al. Crystal Structure of the Human BRD2 Bromodomain: INSIGHTS INTO DIMERIZATION AND RECOGNITION OF ACETYLATED HISTONE H4. Journal of Biological Chemistry. 2006;282(6):4193–201.
+[3]	Umehara T, Nakamura Y, Jang MK, Nakano K, Tanaka A, Ozato K, et al. Structural Basis for Acetylated Histone H4 Recognition by the Human BRD2 Bromodomain. Journal of Biological Chemistry. 2010Apr;285(10):7610–8.
+[4]	Wang Q, Li Y, Xu J, Wang Y, Leung EL-H, Liu L, et al. Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations. Scientific Reports. 2017;7(1).
+[5]	Viejo-Borbolla A, Ottinger M, Bruning E, Burger A, Konig R, Kati E, et al. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's Sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. Journal of Virology. 2005Nov;
+[6]	Gilan O, Rioja I, Knezevic K, Bell M, Yeung M. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020Apr24;368(6489):387–94.
+[7]	Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. BRD2 (RING3) Is a Probable Major Susceptibility Gene for Common Juvenile Myoclonic Epilepsy. The American Journal of Human Genetics. 2003;73(2):261–70.
+[8]	UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain-containing protein 2 [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/P25440#expression
+[9]	UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain-containing protein 3 [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/Q15059
+[10]	UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain-containing protein 4 [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/O60885
+[11]	UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Bromodomain testis-specific protein [Internet]. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. State Secretariat for Education, Research, and Innovation; 2020 [cited 2020Apr28]. Available from: https://www.uniprot.org/uniprot/Q58F21
+[12]	RCSB Protein Data Bank. 2DVQ: Crystal structure analysis of the N-terminal bromodomain of human BRD2 complexed with acetylated histone H4 peptide [Internet]. RCSB PDB. [cited 2020Apr28]. Available from: https://www.rcsb.org/structure/2DVQ
+[13]	Tommaso PD, Moretti S, Xenarios I, Orobitg M, Montanyola A, Chang J-M, et al. T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension. Nucleic Acids Research. 2011Sep;39(suppl).
+[14]	Armougom F, Moretti S, Poirot O, Audic S, Dumas P, Schaeli B, et al. Expresso: automatic incorporation of structural information in multiple sequence alignments using 3D-Coffee. Nucleic Acids Research. 2006Jan;34(Web Server).
+[15]	Osullivan O. 3DCoffee: Combining Protein Sequences and Structures within Multiple Sequence Alignments. Journal of Molecular Biology. 2004;
+[16]	Notredame C, Higgins DG, Heringa J. T-coffee: a novel method for fast and accurate multiple sequence alignment. Thornton J, editor. Journal of Molecular Biology. 2000;302(1):205–17.
+[17] The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.
+[18] 18.	Sievers F, Higgins DG. Clustal Omega, Accurate Alignment of Very Large Numbers of Sequences. Methods in Molecular Biology Multiple Sequence Alignment Methods. 2013;:105–16.
 <references/>