PMID- 14570894
OWN - NLM
STAT- MEDLINE
DCOM- 20040423
LR  - 20220316
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 4
DP  - 2004 Jan 23
TI  - Identification of residues crucially involved in the binding of the heme moiety 
      of soluble guanylate cyclase.
PG  - 3025-32
AB  - Soluble guanylate cyclase (sGC), a heterodimeric hemeprotein, is the only 
      receptor for the biological messenger nitric oxide (NO) identified to date and is 
      intimately involved in various signal transduction pathways. By using the 
      recently discovered NO- and heme-independent sGC activator BAY 58-2667 and a 
      novel cGMP reporter cell, we could distinguish between heme-containing and 
      heme-free sGC in an intact cellular system. Using these novel tools, we 
      identified the invariant amino acids tyrosine 135 and arginine 139 of the 
      beta(1)-subunit as crucially important for both the binding of the heme moiety 
      and the activation of sGC by BAY 58-2667. The heme is displaced by BAY 58-2667 
      due to a competition between the carboxylic groups of this compound and the heme 
      propionic acids for the identified residues tyrosine 135 and arginine 139. This 
      displacement results in the release of the axial heme ligand histidine 105 and to 
      the observed activation of sGC. Based on these findings we postulate a signal 
      transmission triad composed of histidine 105, tyrosine 135, and arginine 139 
      responsible for the enzyme activation by this compound and probably also for 
      transducing changes in heme status and porphyrin geometry upon NO binding into 
      alterations of sGC catalytic activity.
FAU - Schmidt, Peter M
AU  - Schmidt PM
AD  - Institute of Cardiovascular Research, Bayer AG, Aprather Weg 18a, D-42096 
      Wuppertal.
FAU - Schramm, Matthias
AU  - Schramm M
FAU - Schroder, Henning
AU  - Schroder H
FAU - Wunder, Frank
AU  - Wunder F
FAU - Stasch, Johannes-Peter
AU  - Stasch JP
LA  - eng
PT  - Journal Article
DEP - 20031021
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 42VZT0U6YR (Heme)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Cattle
MH  - Enzyme Activation
MH  - Guanylate Cyclase/*chemistry/genetics/metabolism
MH  - Heme/*chemistry/genetics/metabolism
MH  - Humans
MH  - Mice
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Protein Binding
MH  - Protein Conformation
MH  - Rats
MH  - Signal Transduction
MH  - Structure-Activity Relationship
EDAT- 2003/10/23 05:00
MHDA- 2004/04/24 05:00
CRDT- 2003/10/23 05:00
PHST- 2003/10/23 05:00 [pubmed]
PHST- 2004/04/24 05:00 [medline]
PHST- 2003/10/23 05:00 [entrez]
AID - S0021-9258(18)52674-0 [pii]
AID - 10.1074/jbc.M310141200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Jan 23;279(4):3025-32. doi: 10.1074/jbc.M310141200. Epub 2003 
      Oct 21.