Abstract:The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A an… Show more
“…Diffraction data were collected at the Elettra Synchrotron Light Source (Trieste, Italy), XRD1 and XRD2 beamlines. Data were processed, and structures were solved as described elsewhere . Data collection and refinement statistics are reported in Table S3.…”
The bromodomains of BAZ2A and BAZ2B (bromodomain adjacent to zinc finger domain proteins 2) are among the most hard to drug of the 61 human bromodomains. While little is known about the role of BAZ2B, there is strong evidence for the opportunity of targeting BAZ2A in various cancers. Here, a benzimidazole−triazole fragment that binds to the BAZ2A acetyl lysine pocket was identified by a molecular docking campaign and validated by competitive binding assays and X-ray crystallography. Another ligand was observed in close proximity by soaking experiments using the BAZ2A bromodomain preincubated with the benzimidazole−triazole fragment. The crystal structure of BAZ2A with the two ligands was employed to design a few benzimidazole−triazole derivatives with increased affinity. We also present the engineering of a BAZ2A bromodomain mutant for consistent, high-resolution crystallographic studies.
“…Diffraction data were collected at the Elettra Synchrotron Light Source (Trieste, Italy), XRD1 and XRD2 beamlines. Data were processed, and structures were solved as described elsewhere . Data collection and refinement statistics are reported in Table S3.…”
The bromodomains of BAZ2A and BAZ2B (bromodomain adjacent to zinc finger domain proteins 2) are among the most hard to drug of the 61 human bromodomains. While little is known about the role of BAZ2B, there is strong evidence for the opportunity of targeting BAZ2A in various cancers. Here, a benzimidazole−triazole fragment that binds to the BAZ2A acetyl lysine pocket was identified by a molecular docking campaign and validated by competitive binding assays and X-ray crystallography. Another ligand was observed in close proximity by soaking experiments using the BAZ2A bromodomain preincubated with the benzimidazole−triazole fragment. The crystal structure of BAZ2A with the two ligands was employed to design a few benzimidazole−triazole derivatives with increased affinity. We also present the engineering of a BAZ2A bromodomain mutant for consistent, high-resolution crystallographic studies.
“…In addition, the small hepatitis delta antigen (S-HDAg) protein of Hepatitis Delta virus (HDV) imitates histone H3 to interact with the BRD domain of BAZ2B, which allows the virus to hijack the host chromatin remodelers to replicate its RNA genome [ 11 ]. Considering that the BRD domain has emerged as a therapeutic target in diverse diseases, some chemical compounds against the BRD of BAZ2B have been developed [ 5 , 12 , 13 , 14 , 15 , 16 , 17 ]. Figure 1 The TAM domain of BAZ2B.…”
“…The ZA loop could then bend toward the ligand to fulfill the experimentally derived distance restraints ( Figure 2 b). The ZA loop has previously been shown to be highly flexible as inferred from crystallographic studies, 36 , 37 NMR relaxation experiments, 38 and molecular dynamics simulations. 39 , 40 Our findings further support that the ZA loop undergoes large conformational changes and provides structural insight into the closed loop state of the ZA loop in the ligand bound form of the TRIM24 bromodomain.…”
Structure-based drug
discovery (SBDD) largely relies on structural
information from X-ray crystallography because traditional NMR structure
calculation methods are too time consuming to be aligned with typical
drug discovery timelines. The recently developed NMR molecular replacement
(
N
MR
2
) method dramatically reduces the
time needed to generate ligand–protein complex structures using
published structures (apo or holo) of the target protein and treating
all observed NOEs as ambiguous restraints, bypassing the laborious
process of obtaining sequence-specific resonance assignments for the
protein target. We apply this method to two therapeutic targets, the
bromodomain of TRIM24 and the second bromodomain of BRD4. We show
that the
N
MR
2
methodology can guide SBDD
by rationalizing the observed SAR. We also demonstrate that new types
of restraints and selective methyl labeling have the potential to
dramatically reduce “time to structure” and extend the
method to targets beyond the reach of traditional NMR structure elucidation.
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