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

2019 ◽  
Author(s):  
Benjamin G. Horst ◽  
Adam L. Yokom ◽  
Daniel J. Rosenberg ◽  
Kyle L. Morris ◽  
Michal Hammel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Electron Microscopy ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Coiled Coil ◽  
X Ray ◽  
Nitric Oxide Signaling ◽  
Catalytic Domains ◽  
X Ray Scattering ◽  
Cryo Electron Microscopy

AbstractSoluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-lengthManduca sextasGC 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.

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

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Benjamin G Horst ◽  
Adam L Yokom ◽  
Daniel J Rosenberg ◽  
Kyle L Morris ◽  
Michal Hammel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Electron Microscopy ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Coiled Coil ◽  
X Ray ◽  
Nitric Oxide Signaling ◽  
Catalytic Domains ◽  
X Ray Scattering ◽  
Cryo Electron Microscopy

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.

Uncovering the structures of modular polyketide synthases

2015 ◽  
Vol 32 (3) ◽  
pp. 436-453 ◽  
Author(s):  
Kira J. Weissman
Keyword(s):  
Electron Microscopy ◽  
Structural Biology ◽  
Structural Characterization ◽  
Small Angle ◽  
Single Particle ◽  
Polyketide Synthases ◽  
X Ray ◽  
X Ray Scattering ◽  
Cryo Electron Microscopy

This review covers a breakthrough in the structural biology of the gigantic modular polyketide synthases (PKS): the structural characterization of intact modules by single-particle cryo-electron microscopy and small-angle X-ray scattering.

scholarly journals Activation mechanism of human soluble guanylate cyclase by stimulators and activators

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rui Liu ◽  
Yunlu Kang ◽  
Lei Chen
Keyword(s):  
Electron Microscopy ◽  
Guanylate Cyclase ◽  
Drug Target ◽  
Soluble Guanylate Cyclase ◽  
Activation Mechanism ◽  
Active Conformation ◽  
Cryo Electron Microscopy ◽  
Human Soluble Guanylate Cyclase ◽  
Structural Mechanisms ◽  
Sgc Stimulators

AbstractSoluble 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.

scholarly journals Convergent Allostery in Ribonucleotide Reductase

2018 ◽  
Author(s):  
William C. Thomas ◽  
F. Phil Brooks ◽  
Audrey A. Burnim ◽  
John-Paul Bacik ◽  
JoAnne Stubbe ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Ribonucleotide Reductase ◽  
Molecular Basis ◽  
Model Organism ◽  
Activity Regulation ◽  
X Ray ◽  
X Ray Scattering ◽  
Cryo Electron Microscopy ◽  
Ribonucleotide Reductases ◽  
Class Ib

AbstractRibonucleotide reductases (RNRs) use a conserved radical-based mechanism to catalyze the conversion of ribonucleotides to deoxyribonucleotides. Within the RNR family, class Ib RNRs are notable for being largely restricted to bacteria, including many pathogens, and for lacking an evolutionarily mobile ATP-cone domain that allosterically controls overall activity. In this study, we report the emergence of a new and unexpected mechanism of activity regulation in the sole RNR of the model organism Bacillus subtilis. Using a hypothesis-driven structural approach that combines the strengths of small-angle X-ray scattering (SAXS), crystallography, and cryo-electron microscopy (cryo-EM), we describe the reversible interconversion of six unique structures, including a flexible, active tetramer and two novel, inhibited filaments. These structures reveal the conformational gymnastics necessary for RNR activity and the molecular basis for its control via an evolutionarily convergent form of allostery.

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