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Related Concept Videos

GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...

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Comparing the Affinity of GTPase-binding Proteins using Competition Assays
10:37

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Published on: October 8, 2015

Enzyme closure and nucleotide binding structurally lock guanylate kinase.

Olivier Delalande1, Sophie Sacquin-Mora, Marc Baaden

  • 1Institut de Biologie Physico-Chimique, Laboratoire de Biochimie Théorique, Centre National de la Recherche Scientifique, UPR9080, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Biophysical Journal
|September 28, 2011
PubMed
Summary

Guanylate kinase (GK) undergoes significant conformational changes influenced by nucleotides. Our study reveals a structural lock stabilizing the closed enzyme form, crucial for its function.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • Guanylate kinase (GK) is an enzyme that undergoes large conformational changes between open and closed states.
  • These conformational changes are influenced by the binding of nucleotides and are essential for enzymatic activity.
  • Understanding the dynamics of GK is crucial for elucidating its reaction mechanism.

Purpose of the Study:

  • To investigate the conformational dynamics and mechanical properties of guanylate kinase (GK).
  • To elucidate the closure mechanism of GK and the hierarchy of structural events involved.
  • To understand how bound ligands modulate GK's properties and identify functionally important differences between states.

Main Methods:

  • Multiscale simulation approach combining atomistic molecular dynamics and Brownian dynamics.
  • Investigation of various GK forms: open-versus-closed, apo-versus-holo, and substrate-versus-product-loaded.
  • Analysis of mechanical properties and rigidity profiles of different GK states.

Main Results:

  • Bound ligands significantly modulate the mechanical and dynamical properties of GK.
  • Rigidity profiles reveal functionally important differences between open and closed states.
  • Identified a water channel for active site hydration and a structural lock stabilizing the closed form.
  • Emphasized the role of magnesium in GK function.

Conclusions:

  • GK exhibits large, nucleotide-influenced conformational changes critical for its enzymatic function.
  • The study provides a detailed picture of GK's closure mechanism and the structural events involved.
  • A structural lock and a hydration channel are key features stabilizing the active closed conformation of GK.