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Related Experiment Video

Updated: Jul 12, 2026

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

Published on: June 23, 2026

Geometry-dependent interfaces shape NLRP3 pyrin domain assembly.

Mehri Javid¹, Alexander Dömling², Maryam Nikkhah³

¹Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

International Journal of Biological Macromolecules

|July 9, 2026

Summary

NLRP3 inflammasome assembly is controlled by the geometry of pyrin domain (PYD) interactions. This study reveals two distinct PYD geometries, explaining how mutations impact NLRP3 inflammasome regulation and signaling.

Keywords:

CAPS-associated mutations Homotypic PYD assembly Interfacial geometry Molecular dynamics simulations NLRP3 inflammasome Protein–protein interactions Pyrin domain (PYD)Structure-guided modulation

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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Published on: May 22, 2014

Area of Science:

Immunology
Structural Biology
Molecular Biology

Background:

NLRP3 inflammasome activation depends on regulated pyrin domain (PYD) interactions.
Understanding the balance between restrained and assembly-competent PYD states is crucial for preventing aberrant signaling.

Purpose of the Study:

To define the geometry-dependent regulation of NLRP3 PYD self-association.
To elucidate how interfacial organization dictates PYD assembly and inflammasome activation.

Main Methods:

Atomistic molecular dynamics simulations
Targeted mutagenesis
Heterotypic native/mutant split-luciferase complementation assays
ASC recruitment assays
Microscale thermophoresis
Mass photometry

Main Results:

Identified two distinct PYD-PYD geometries: a restrained Type A-like dimer and a filament-compatible Type B-like geometry.
Demonstrated that functional differences arise from interfacial organization, not global structural changes.
Showed that specific mutations (S5D, D31V, D21H) differentially remodel PYD assembly through distinct mechanisms.

Conclusions:

NLRP3 PYD self-association is a geometry-dependent process governed by specific networks.
This framework offers structural insights into regulatory modifications and CAPS mutations.
NLRP3 PYD interfaces represent potential targets for modulating inflammasome signaling.