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Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
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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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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
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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...
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Ligand Binding and Linkage00:49

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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The eptinezumab:CGRP complex structure - the role of conformational changes in binding stabilization.

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Eptinezumab binds calcitonin gene-related peptide (CGRP) via a unique

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Area of Science:

  • Structural Biology
  • Biochemistry
  • Pharmacology

Background:

  • Calcitonin gene-related peptide (CGRP) is a key mediator in migraine pathophysiology.
  • Eptinezumab is a monoclonal antibody targeting CGRP for migraine prevention.

Purpose of the Study:

  • To elucidate the molecular mechanism and binding characteristics of eptinezumab to CGRP.
  • To understand the structural basis for eptinezumab's efficacy in migraine prevention.

Main Methods:

  • X-ray crystallography to determine 3D structures of eptinezumab's antigen-binding fragment (Fab) and its complex with CGRP.
  • Molecular dynamics simulations to analyze binding transitions.
  • Computational alanine scanning to identify key binding residues on CGRP.

Main Results:

  • Eptinezumab's Fab binds the amidated C-terminus of CGRP within a specific pocket.
  • Extensive interactions involve all six complementarity-determining regions (CDRs) and aromatic residues.
  • Conformational changes in CDRs H2 and H3 create a 'latch-and-lock' mechanism, enhancing binding stability.
  • Computational alanine scanning identified critical CGRP residues essential for high-affinity binding.

Conclusions:

  • Eptinezumab's binding to CGRP is characterized by extensive contacts and induced conformational changes.
  • The 'latch-and-lock' mechanism and specific residue interactions contribute to the drug's specificity, durability, and strength.
  • These molecular attributes likely explain the rapid and sustained migraine preventive effects observed clinically.