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Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy

Journal Article · · eLife
DOI:https://doi.org/10.7554/eLife.50634· OSTI ID:1591813
 [1];  [1];  [2];  [1];  [3];  [4];  [1]
  1. Univ. of California, Berkeley, CA (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1591813
Journal Information:
eLife, Journal Name: eLife Vol. 8; ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.Copyright Statement
Country of Publication:
United States
Language:
English

References (78)

The Chemistry and Biology of Soluble Guanylate Cyclase Stimulators and Activators journal August 2013
UCSF Chimera?A visualization system for exploratory research and analysis journal January 2004
Crystal structure of the Alpha subunit PAS domain from soluble guanylyl cyclase: Crystal Structure of the Alpha Subunit PAS Domain from sGC journal September 2013
Salt bridges: Geometrically specific, designable interactions journal January 2011
BAY 41-2272 Activates Two Isoforms of Nitric Oxide- Sensitive Guanylyl Cyclase journal April 2002
Protein secondary structure prediction based on position-specific scoring matrices 1 1Edited by G. Von Heijne journal September 1999
High-Throughput SAXS for the Characterization of Biomolecules in Solution: A Practical Approach book October 2013
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen journal August 2020
Nitric oxide as modulator of neuronal function journal May 2001
The adenylyl and guanylyl cyclase superfamily journal December 1998
Loss of α1β1 Soluble Guanylate Cyclase, the Major Nitric Oxide Receptor, Leads to Moyamoya and Achalasia journal March 2014
Loss of α1β1 Soluble Guanylate Cyclase, the Major Nitric Oxide Receptor, Leads to Moyamoya and Achalasia journal April 2014
Accurate SAXS Profile Computation and its Assessment by Contrast Variation Experiments journal August 2013
RELION: Implementation of a Bayesian approach to cryo-EM structure determination journal December 2012
CTFFIND4: Fast and accurate defocus estimation from electron micrographs journal November 2015
The function of NO-sensitive guanylyl cyclase: What we can learn from genetic mouse models journal December 2009
Physiological activation and deactivation of soluble guanylate cyclase journal July 2018
Nitric Oxide-Induced Conformational Changes in Soluble Guanylate Cyclase journal April 2014
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution journal August 2007
Soluble Guanylate Cyclase from Bovine Lung: Activation with Nitric Oxide and Carbon Monoxide and Spectral Characterization of the Ferrous and Ferric States journal May 1994
Expression and Characterization of the Catalytic Domains of Soluble Guanylate Cyclase:  Interaction with the Heme Domain journal March 2005
Aspartate 102 in the Heme Domain of Soluble Guanylyl Cyclase Has a Key Role in NO Activation journal May 2011
Molecular Model of a Soluble Guanylyl Cyclase Fragment Determined by Small-Angle X-ray Scattering and Chemical Cross-Linking journal February 2013
Interfacial Residues Promote an Optimal Alignment of the Catalytic Center in Human Soluble Guanylate Cyclase: Heterodimerization Is Required but Not Sufficient for Activity journal March 2014
Characterization of Two Different Five-Coordinate Soluble Guanylate Cyclase Ferrous–Nitrosyl Complexes journal March 2008
Identification of Histidine 105 in the β1 Subunit of Soluble Guanylate Cyclase as the Heme Proximal Ligand journal March 1998
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor journal June 1987
Structure of the adenylyl cyclase catalytic core journal March 1997
Erratum: Structure of the adenylyl cyclase catalytic core journal July 1997
Accurate assessment of mass, models and resolution by small-angle scattering journal April 2013
Regulation of nitric oxide signaling by formation of a distal receptor–ligand complex journal October 2017
Robust, high-throughput solution structural analyses by small angle X-ray scattering (SAXS) journal July 2009
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination journal February 2017
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy journal February 2017
The Phyre2 web portal for protein modeling, prediction and analysis journal May 2015
Strategies to increase nitric oxide signalling in cardiovascular disease journal August 2015
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome journal December 2019
Structural insights into the mechanism of human soluble guanylate cyclase journal September 2019
Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5 journal March 2021
NO activation of guanylyl cyclase journal October 2004
Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases journal August 2004
Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by nonheme nitric oxide, ATP, and GTP journal August 2005
A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase journal December 2009
Higher-order interactions bridge the nitric oxide receptor and catalytic domains of soluble guanylate cyclase journal April 2013
Single-particle EM reveals the higher-order domain architecture of soluble guanylate cyclase journal February 2014
Structural insights into the role of iron–histidine bond cleavage in nitric oxide-induced activation of H-NOX gas sensor proteins journal September 2014
Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation journal October 2017
Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations journal August 1977
A molecular basis for nitric oxide sensing by soluble guanylate cyclase journal December 1999
Structure, Mechanism, and Regulation of Mammalian Adenylyl Cyclase journal March 1999
Allostery in Recombinant Soluble Guanylyl Cyclase from Manduca sexta journal May 2008
Discovery of stimulator binding to a conserved pocket in the heme domain of soluble guanylyl cyclase journal December 2017
Endogenous nitric oxide synthesis: Biological functions and pathophysiology journal January 1999
Structure and Activation of Soluble Guanylyl Cyclase, the Nitric Oxide Sensor journal January 2017
FoXS: a web server for rapid computation and fitting of SAXS profiles journal May 2010
FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles journal May 2016
geopandas/geopandas: v0.8.1 posted_content July 2020
Implementation and performance of SIBYLS: a dual endstation small-angle X-ray scattering and macromolecular crystallography beamline at the Advanced Light Source journal January 2013
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Features and development of Coot journal March 2010
Software for the high-throughput collection of SAXS data using an enhanced Blu-Ice / DCS control system journal September 2010
Modeling of loops in protein structures journal January 2000
Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension: Disrupted nitric oxide signaling due to GUCY1A3 mutations journal February 2016
Crystal Structure of the Catalytic Domains of Adenylyl Cyclase in a Complex with Gs·GTPS journal December 1997
The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein journal April 2019
Structure and Regulation of Soluble Guanylate Cyclase journal July 2012
Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease journal May 2011
YC-1, a novel activator of platelet guanylate cyclase journal December 1994
Crystal structure of the signaling helix coiled-coil domain of the β1 subunit of the soluble guanylyl cyclase journal January 2010
The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase journal January 2008
Nitric oxide: A pleiotropic signal in the nervous system journal October 2011
Identification of Residues in the Heme Domain of Soluble Guanylyl Cyclase that are Important for Basal and Stimulated Catalytic Activity journal November 2011
Crystal Structures of the Catalytic Domain of Human Soluble Guanylate Cyclase journal March 2013
Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation text January 2017
Structure and flexibility within proteins as identified through small angle X-ray scattering journal January 2009
The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein text January 2019
A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice journal June 2018
Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION journal June 2018

Cited By (4)

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development journal December 2019
Synergistic mutations in soluble guanylyl cyclase (sGC) reveal a key role for interfacial regions in the sGC activation mechanism journal October 2019
The cGMP system: components and function journal March 2020
Wedging open a catalytic site journal November 2019

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