Sandbox Reserved 896: Difference between revisions

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Figure 1: Surface view of BD1 homo-2-mer binding N-acetyl-lysine 12 of histone H4. Produced by PyMol.

== Structure ==

The BRD2 protein consists of three domains: C-terminal bromodomain 1 (BD1), bromodomain 2 (BD2), and N-extra-terminal domain. As BD1 plays the primary role in coordinating the N-acetyl-lysine ligand, this domain’s structure is of the most functional importance.

BD1 Structure

- Contains a left-handed alpha-helical bundle formed by four alpha helices: aZ, aA, aB, and aC

- Structure is similar to bromodomains of p300/CBP-associated factor (PCAF), GCN5, double bromodomain module of TAF1

- The active site of BD1 is a deep cleft consisting of a ZA loop (extended long loop which is named so due to connecting the aZ and aA helices) and a BC loop (another loop which connects aB and aC loops).

- Hydrophobic core is mostly stabilized by conserved hydrophobic and few hydrophilic residues

BD1 vs. BD2 Drug Selectivity

- Genetic divergence between structure of ZA and BC loops in BD1 vs. BD2 is what allows selective drug targeting of one bromodomain

- In BD1, the shortest communication path between ZA and BC loops is a chain consisting of Leu110  Tyr113  Ile117  Asn151  Tyr153  Asn156 [4].

- In BD2, the shortest communication path between ZA and BC loops is a chain consisting of Leu383  Asp385  Ile 389  Tyr428  Asn429c [4].

- The precise mechanism for which this selection occurs is unknown, but it is known that Leu383 and Asn429 are the two most important residues of BD2 that allow binding of the RVX-208 inhibitor molecule [4].

- ABBC-744 is another preclinical inhibitor that takes advantage of this divergence.

~~== Structure ==~~

[[Image:ProteopediaTest.png]]

[[Image:ProteopediaTest.png]] Figure 2: Tertiary Structure of dimerized BRD2 protein.

== Medical Relevance ==

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@@ Line 14: / Line 14: @@
 Figure 1: Surface view of BD1 homo-2-mer binding N-acetyl-lysine 12 of histone H4. Produced by PyMol.
+== Structure ==
+The BRD2 protein consists of three domains: C-terminal bromodomain 1 (BD1), bromodomain 2 (BD2), and N-extra-terminal domain. As BD1 plays the primary role in coordinating the N-acetyl-lysine ligand, this domain’s structure is of the most functional importance.
+BD1 Structure
+-	Contains a left-handed alpha-helical bundle formed by four alpha helices: aZ, aA, aB, and aC
+-	Structure is similar to bromodomains of p300/CBP-associated factor (PCAF), GCN5, double bromodomain module of TAF1
+-	The active site of BD1 is a deep cleft consisting of a ZA loop (extended long loop which is named so due to connecting the aZ and aA helices) and a BC loop (another loop which connects aB and aC loops).
+-	Hydrophobic core is mostly stabilized by conserved hydrophobic and few hydrophilic residues
+BD1 vs. BD2 Drug Selectivity
+-	Genetic divergence between structure of ZA and BC loops in BD1 vs. BD2 is what allows selective drug targeting of one bromodomain
+-	In BD1, the shortest communication path between ZA and BC loops is a chain consisting of Leu110  Tyr113  Ile117  Asn151  Tyr153  Asn156 [4].
+-	In BD2, the shortest communication path between ZA and BC loops is a chain consisting of Leu383  Asp385  Ile 389  Tyr428  Asn429c [4].
+-	The precise mechanism for which this selection occurs is unknown, but it is known that Leu383 and Asn429 are the two most important residues of BD2 that allow binding of the RVX-208 inhibitor molecule [4].
+-	ABBC-744 is another preclinical inhibitor that takes advantage of this divergence.
-== Structure ==
-[[Image:ProteopediaTest.png]]
+[[Image:ProteopediaTest.png]] Figure 2: Tertiary Structure of dimerized BRD2 protein.
 == Medical Relevance ==