A possible allosteric site.

<p>A. Forskolin in its binding pocket in adenylate cyclase. B. The same region in sGC in the crystal structure: the cavity is collapsed, with no space for small-molecule binding. C. sGC in the modelled active conformation: a cavity opens up; although forskolin does not fit, other small molecules may occupy the site.</p

Crystallographic statistics.

<p>Crystallographic statistics.</p

Active site residues on sGC in the modelled active conformation.

<p>The sGCα and sGCβ were separately aligned with AC domains C1 and C2, respectively. A. Overall view (the colour scheme is described in panel C). C. Active site residues surrounding an ATP analogue in the AC structure. C, D. Detailed views.</p

Overview of crystal structures.

<p>A. Homodimer of sGCβ catalytic domain (PDB ID: 2WZ1). B. Heterodimer of sGCα (green) and sGCβ (cyan) catalytic domains (PDB ID: 3UVJ). C. Architecture of the sGCα catalytic domain. D. Architecture of the sGCβ catalytic domain. E. The β4–5 loop in AC-C1 (purple) and sGCα (green); the surface of the β/C2 subunit is shown in cyan.</p

Structural transitions in sGC activation.

<p>A. sGCα in the crystal structure (green) compared with the same subunit (orange) modelled by alignment with the C1 domain of adelylate cyclase (purple). The rigid-body transition involves a 26° rotation, seen in the relative angles of the corresponding α helices. B. Detail: the change in position of the α1 helix (sGCα), bringing it closer to helix α4 (sGCβ). C. Detail: shift in position of the β6–7 loop, which brings a catalyitic residue D530 closer to the position of the corresponding residue in AC(D440).</p

Human Pleckstrin Homology domain Interacting Protein (PHIP); A Target Enabling Package

<p>SGC Oxford has expressed, purified and crystallized the second bromodomain of PHIP as part of the probe programme. Fragment screening and X-ray crystallography identified binders, some of which optimised to uM affinity. However, molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p

Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin

Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain

Human Pleckstrin Homology domain Interacting Protein (PHIP); A Target Enabling Package

<p>SGC Oxford has expressed, purified and crystallized the second bromodomain of PHIP as part of the probe programme. Fragment screening and X-ray crystallography identified binders, some of which optimised to uM affinity. However, molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p

Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin

Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain

Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2/7 Histone Demethylases

The JmjC oxygenases catalyze the <i>N</i>-demethylation of <i>N</i>^ε-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (<i>N-</i>(dimethylamino)­succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups