PMID- 23505436
OWN - NLM
STAT- MEDLINE
DCOM- 20130906
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 3
DP  - 2013
TI  - Crystal structures of the catalytic domain of human soluble guanylate cyclase.
PG  - e57644
LID - 10.1371/journal.pone.0057644 [doi]
LID - e57644
AB  - Soluble guanylate cyclase (sGC) catalyses the synthesis of cyclic GMP in response 
      to nitric oxide. The enzyme is a heterodimer of homologous alpha and beta subunits, each 
      of which is composed of multiple domains. We present here crystal structures of a 
      heterodimer of the catalytic domains of the alpha and beta subunits, as well as an 
      inactive homodimer of beta subunits. This first structure of a metazoan, heteromeric 
      cyclase provides several observations. First, the structures resemble known 
      structures of adenylate cyclases and other guanylate cyclases in overall fold and 
      in the arrangement of conserved active-site residues, which are contributed by 
      both subunits at the interface. Second, the subunit interaction surface is 
      promiscuous, allowing both homodimeric and heteromeric association; the 
      preference of the full-length enzyme for heterodimer formation must derive from 
      the combined contribution of other interaction interfaces. Third, the 
      heterodimeric structure is in an inactive conformation, but can be superposed 
      onto an active conformation of adenylate cyclase by a structural transition 
      involving a 26 degrees  rigid-body rotation of the alpha subunit. In the modelled active 
      conformation, most active site residues in the subunit interface are precisely 
      aligned with those of adenylate cyclase. Finally, the modelled active 
      conformation also reveals a cavity related to the active site by pseudo-symmetry. 
      The pseudosymmetric site lacks key active site residues, but may bind allosteric 
      regulators in a manner analogous to the binding of forskolin to adenylate 
      cyclase. This indicates the possibility of developing a new class of 
      small-molecule modulators of guanylate cyclase activity targeting the catalytic 
      domain.
FAU - Allerston, Charles K
AU  - Allerston CK
AD  - Structural Genomics Consortium, University of Oxford, Oxford, The United Kingdom.
FAU - von Delft, Frank
AU  - von Delft F
FAU - Gileadi, Opher
AU  - Gileadi O
LA  - eng
GR  - Wellcome Trust/United Kingdom
GR  - 092809/Wellcome Trust/United Kingdom
GR  - 092809/ /10/Z/WT_/Wellcome Trust/United Kingdom
GR  - CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130307
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amino Acids)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Recombinant Proteins)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
SB  - IM
MH  - Allosteric Regulation
MH  - Amino Acids/chemistry
MH  - *Catalytic Domain
MH  - Enzyme Activation
MH  - Guanylate Cyclase/*chemistry/genetics/metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Protein Conformation
MH  - Protein Interaction Domains and Motifs
MH  - Protein Multimerization
MH  - Protein Subunits
MH  - Receptors, Cytoplasmic and Nuclear/*chemistry/genetics/metabolism
MH  - Recombinant Proteins
MH  - Soluble Guanylyl Cyclase
PMC - PMC3591389
COIS- Competing Interests: The authors have the following interests. This study was 
      funded by The SGC which is a charity funded by a public-private partnership that 
      includes commercial entities (GlaxoSmithKline, Lilly Canada, the Novartis 
      Research Foundation, Pfizer, Takeda, and AbbVie). There are no patents, products 
      in development or marketed products to declare. This does not alter the authors' 
      adherence to all the PLOS ONE policies on sharing data and materials, as detailed 
      online in the guide for authors.
EDAT- 2013/03/19 06:00
MHDA- 2013/09/07 06:00
PMCR- 2013/03/07
CRDT- 2013/03/19 06:00
PHST- 2012/10/10 00:00 [received]
PHST- 2013/01/22 00:00 [accepted]
PHST- 2013/03/19 06:00 [entrez]
PHST- 2013/03/19 06:00 [pubmed]
PHST- 2013/09/07 06:00 [medline]
PHST- 2013/03/07 00:00 [pmc-release]
AID - PONE-D-12-35096 [pii]
AID - 10.1371/journal.pone.0057644 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(3):e57644. doi: 10.1371/journal.pone.0057644. Epub 2013 Mar 7.