Guanylyl cyclases
A majority of today's medicines act via receptors, either membrane bound or soluble receptors. These receptors are
the communication portals for cells with mostly signals going into the cell but sometimes also signaling from the inside-out. Our lab is
mainly focusing
on the soluble guanylyl cyclase (sGC) receptor as well
as the atrial natriuretic peptide receptor. Both receptors are guanylyl cyclases (GC) and
wonderful complex signal transduction systems to probe scientifically with the strong potential of generating mechanistic insights that can be pharmaceutically exploited.
These receptors are guanylyl cyclase receptors involved numerous physiological processes including blood pressure
regulation and as such have received strong pharmaceutical attention as they are both drug targets. Our lab is one of the world leaders in GC structural biology having
crystallographically
characterized 4 different domains of guanylyl cyclases or homologs thereof: 1) heme-nitric-oxide-oxygen binding domain (H-NOX) homologous to sGC in
complex with NO and CO (Ma et al., EMBO J 2007);
2) H-NOX-associated domain (H-NOXA) dimer homologous to sGC revealing a PAS-fold (Ma et al., JBC 2008)
 ;
3) sGC’s coiled-coil (CC) domain (Ma et al., BMC Struct. Biol. 2010)
 ;
4) membrane GC’s atrial natriuretic peptide (ANP) receptor hormone
binding domain (van den Akker et al., Nature 2000)
 .
Our results gained new mechanistic insights into the structure and
activation of these receptors and can be used to develop novel therapeutic modulators for cardiovascular diseases or other repercussions of impaired GC signaling.
All of these steps are structurally not well understood making these receptors ideal candidates for
a concerted multi-disciplinary approach to gain mechanistic insights.
We have previously determined the crystal structure of the ligand binding domain of the
atrial natriuretic peptide receptor revealing many unexpected discoveries such as its structural similarity with periplasmic binding
proteins, possible dual allosteric regulation, the hormone binding site, and dimer interfaces.
Our current projects range from relatively straight forward experiments such as site-directed
mutagenesis and activity assays to probe specific questions, to biochemically characterizing and crystallizing the remaining
individual domains, to our most ambitious long term goals of crystallizing the entire receptor and discovering new pharmaceutically
interesting effectors based on our structural investigations.
Click here to view structure or download coordinates.
In addition, we have in collaboration with the Warman lab, identified 12 human mutations in the c-type natriuretic peptide receptor (NPR-B or GC-B). Patients
with these mutations have a dwarf-like phenotype.
Our lab has enzymatically characterized a number of these mutants as well as generated a homology model
for the entire full length NPR-B receptor. This work was published recently in
Am. J. Human Genetics (click on Publications to find references).
Please click here to visit Dr. Matthew Warman's lab website Warman website
Our lab has determined the structure of a sGC activator bound to the heme domain revealing insights into the activation
of sGC. This sGC activator, BAY58-2667, is in clinical trials for decompensated heart failure and the insights gained from our structure could lead to improvements into the design
of this class of activators
 .
This work was in collaboration with the labs of Beuve (at UMDNJ) and Stasch (at Bayer) and was recently published in JBC
(Martin et al. 2010). A previous collaborative publication in PNAS revealed that desensitization of sGC can occur via S-nitrosylation with a likely involvement of a cysteine within
the H-NOX domain (Sayed et al, 2007).
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