|Entry||Database: PDB / ID: 7d9r|
|Title||Structure of huamn soluble guanylate cyclase in the riociguat and NO-bound state|
|Components||(Guanylate cyclase soluble subunit ...) x 2|
|Keywords||SIGNALING PROTEIN / soluble guanylate cyclase|
|Function / homology|
Function and homology information
retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / cGMP biosynthetic process / guanylate cyclase / guanylate cyclase activity / Nitric oxide stimulates guanylate cyclase / blood circulation / relaxation of vascular associated smooth muscle / cGMP-mediated signaling ...retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / cGMP biosynthetic process / guanylate cyclase / guanylate cyclase activity / Nitric oxide stimulates guanylate cyclase / blood circulation / relaxation of vascular associated smooth muscle / cGMP-mediated signaling / presynaptic active zone / nitric oxide-cGMP-mediated signaling pathway / Smooth Muscle Contraction / GABA-ergic synapse / cellular response to nitric oxide / positive regulation of nitric oxide mediated signal transduction / nitric oxide mediated signal transduction / regulation of blood pressure / signaling receptor activity / glutamatergic synapse / GTP binding / heme binding / metal ion binding
Similarity search - Function
Haem NO binding associated domain superfamily / Haem NO binding associated / Heme NO binding associated / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Heme NO-binding / H-NOX domain superfamily / Haem-NO-binding / NO signalling/Golgi transport ligand-binding domain superfamily / Adenylyl- / guanylyl cyclase, catalytic domain ...Haem NO binding associated domain superfamily / Haem NO binding associated / Heme NO binding associated / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Heme NO-binding / H-NOX domain superfamily / Haem-NO-binding / NO signalling/Golgi transport ligand-binding domain superfamily / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / Nucleotide cyclase
Similarity search - Domain/homology
Guanylate cyclase soluble subunit alpha-1 / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / Chem-GZO / PROTOPORPHYRIN IX CONTAINING FE / Guanylate cyclase soluble subunit beta-1
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å|
|Authors||Chen, L. / Liu, R. / Kang, Y.|
|Funding support|| China, 4items |
|Citation||Journal: Nat Commun / Year: 2021|
Title: Activation mechanism of human soluble guanylate cyclase by stimulators and activators.
Authors: Rui Liu / Yunlu Kang / Lei Chen /
Abstract: Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by ...Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 and riociguat, and also in complex with the activator cinaciguat. These structures uncover the molecular details of how stimulators interact with residues from both β H-NOX and CC domains, to stabilize sGC in the extended active conformation. In contrast, cinaciguat occupies the haem pocket in the β H-NOX domain and sGC shows both inactive and active conformations. These structures suggest a converged mechanism of sGC activation by pharmacological compounds.
|Structure viewer||Molecule: |
Downloads & links
A: Guanylate cyclase soluble subunit alpha-1
B: Guanylate cyclase soluble subunit beta-1
-Guanylate cyclase soluble subunit ... , 2 types, 2 molecules A
|#1: Protein|| |
Mass: 77566.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: GenBank: AAH28384.1 / Source: (gene. exp.) Homo sapiens (human) / Gene: GUCY1A1, GUC1A3, GUCSA3, GUCY1A3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02108, guanylate cyclase
|#2: Protein|| |
Mass: 70599.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GUCY1B1, GUC1B3, GUCSB3, GUCY1B3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02153, guanylate cyclase
-Non-polymers , 4 types, 5 molecules
|#3: Chemical|| ChemComp-G2P / |
|#4: Chemical||#5: Chemical|| ChemComp-HEM / ||#6: Chemical|| ChemComp-GZO / |
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: human soluble guanylate cyclaseSoluble guanylyl cyclase|
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Spodoptera frugiperda (fall armyworm)|
|Buffer solution||pH: 7.5|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)|
|Software||Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement|
|EM software||Name: RELION / Version: 3 / Category: 3D reconstruction|
|CTF correction||Type: NONE|
|3D reconstruction||Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 215573 / Symmetry type: POINT|
|Refinement||Resolution: 3.3→229.9 Å / SU ML: 1.09 / σ(F): 0.27 / Phase error: 47.98 / Stereochemistry target values: MLHL / |
|Solvent computation||Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL|
|Refine LS restraints|
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