High-resolution crystal structures of factor XIa coagulation factor in complex with nonbasic high-affinity synthetic...

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Factor XI (FXI) is a crucial enzyme in the blood coagulation cascade.
• FXI is a promising target for novel anticoagulant drug development.
• Existing FXIa crystal structures show inhibitors binding to the nonprime side of the active site.

Purpose of the Study:

• To present novel high-resolution crystal structures of Factor XIa (FXIa) in complex with nonbasic inhibitors.
• To characterize the binding interactions of these new inhibitors within the FXIa active site.
• To provide structural insights for the design of next-generation FXIa inhibitors.

Main Methods:

• X-ray crystallography was used to determine the structures of FXIa-inhibitor complexes.
• High-resolution structural data was obtained and analyzed.
• Comparative analysis with existing FXIa-inhibitor structures was performed.

Main Results:

• Two new crystal structures of FXIa complexed with nonbasic inhibitors were determined.
• These inhibitors occupy both the prime and nonprime sides of the FXIa active site.
• The binding mode differs from previously reported inhibitors with basic P1 groups.

Conclusions:

• The presented structures offer new insights into FXIa active site interactions.
• Nonbasic inhibitors binding across both prime and nonprime sides are feasible.
• These findings can guide the optimization of FXIa inhibitors for anticoagulant therapy.