5UBM

Crystal structure of human C1s in complex with inhibitor gigastasin

Summary for 5UBM

• Entry DOI: 10.2210/pdb5ubm/pdb
• Descriptor: Complement C1s subcomponent, Gigastasin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: complement system c1s protease inhibitor complex, immune system-inhibitor complex, immune system/inhibitor
• Biological source: Haementeria ghilianii; More
• Total number of polymer chains: 3
• Total formula weight: 61253.12

Authors

Pang, S.S.,Whisstock, J.C. (deposition date: 2016-12-20, release date: 2017-11-08, Last modification date: 2024-11-06)

Primary citation

Pang, S.S.,Wijeyewickrema, L.C.,Hor, L.,Tan, S.,Lameignere, E.,Conway, E.M.,Blom, A.M.,Mohlin, F.C.,Liu, X.,Payne, R.J.,Whisstock, J.C.,Pike, R.N.
The Structural Basis for Complement Inhibition by Gigastasin, a Protease Inhibitor from the Giant Amazon Leech.
J. Immunol., 199:3883-3891, 2017

PubMed Abstract: Complement is crucial to the immune response, but dysregulation of the system causes inflammatory disease. Complement is activated by three pathways: classical, lectin, and alternative. The classical and lectin pathways are initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases. Given the role of complement in disease, there is a requirement for inhibitors to control the initiating proteases. In this article, we show that a novel inhibitor, gigastasin, from the giant Amazon leech, potently inhibits C1s and MASP-2, whereas it is also a good inhibitor of MASP-1. Gigastasin is a poor inhibitor of C1r. The inhibitor blocks the active sites of C1s and MASP-2, as well as the anion-binding exosites of the enzymes via sulfotyrosine residues. Complement deposition assays revealed that gigastasin is an effective inhibitor of complement activation in vivo, especially for activation via the lectin pathway. These data suggest that the cumulative effects of inhibiting both MASP-2 and MASP-1 have a greater effect on the lectin pathway than the more potent inhibition of only C1s of the classical pathway.

PubMed: 29061764
DOI: 10.4049/jimmunol.1700158

Experimental method

X-RAY DIFFRACTION (2.5 Å)