Table 2. In-depth breakdown of NLRP3 structure, including key motifs and their roles.

S. N.	Domain	Location	Function	Key interactions	Structural features	References
1	Pyrin domain (PYD)	N-terminal (1–92)	Facilitates protein–protein interactions via homotypic PYD–PYD binding; essential for ASC recruitment	Binds ASC to form an inflammasome complex	Alpha-helical fold: death domain super family	49
2	Walker A motif (P-loop)	NACHT domain	Binds ATP and facilitates hydrolysis for conformational changes	Essential for ATPase activity	Conserved GxxxxGKT/S sequence	50
3	Walker B motif	NACHT domain	Coordinates Mg2+ and hydrolyzes ATP to drive NLRP3 activation	Required for ATPase-dependent activation	Contains hydrophobic residues and aspartate	51
4	Sensor II motif	NACHT domain	Regulates ATPase activity by stabilizing the protein conformation	Modulates ATP hydrolysis	Found near Walker B motif	52
5	Nucleotide-binding and oligomerization domain (NACHT)	Central (120–436)	ATPase activity; responsible for NLRP3 oligomerization and activation	Interacts with NEK7 for oligomerization	Contains Walker A/B motifs for ATP binding	53
6	Helical domain (HD1 & HD2)	Between NACHT and LRR	Acts as a structural bridge between NACHT and LRR, involved in NLRP3 conformational dynamics	Modulates auto inhibition	Alpha-helical bundles	17
7	Leucine-rich repeat (LRR) domain	C-terminal (600–1036)	Regulates NLRP3 activation, possibly through auto inhibition by folding onto NACHT domain	Binds various PAMPs/DAMPs, interacts with NEK7	Composed of tandem leucine-rich repeats	54