8gmn

From Proteopedia

Crystal structure of human C1s in complex with inhibitor

Structural highlights

8gmn is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

C1S_HUMAN Defects in C1S are the cause of complement component C1s deficiency (C1SD) [MIM:613783. A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis.

Function

C1S_HUMAN C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4.

Publication Abstract from PubMed

A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit 3, isoquinoline was replaced with 1-aminophthalazine to enhance C1s inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure of a complex of C1s and a small-molecule inhibitor (4e), which guided structure-based optimization around the S2 and S3 sites to further enhance C1s inhibitory activity by over 300-fold. Improvement of membrane permeability by incorporation of fluorine at the 8-position of 1-aminophthalazine led to identification of (R)-8 as a potent, selective, orally available, and brain-penetrable C1s inhibitor. (R)-8 significantly inhibited membrane attack complex formation induced by human serum in a dose-dependent manner in an in vitro assay system, proving that selective C1s inhibition blocked the classical complement pathway effectively. As a result, (R)-8 emerged as a valuable tool compound for both in vitro and in vivo assessment.

Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.,Ikeda Z, Kamei T, Sasaki Y, Reynolds M, Sakai N, Yoshikawa M, Tawada M, Morishita N, Dougan DR, Chen CH, Levin I, Zou H, Kuno M, Arimura N, Kikukawa Y, Kondo M, Tohyama K, Sato K J Med Chem. 2023 May 11;66(9):6354-6371. doi: 10.1021/acs.jmedchem.3c00348. Epub , 2023 Apr 25. PMID:37120845^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ikeda Z, Kamei T, Sasaki Y, Reynolds M, Sakai N, Yoshikawa M, Tawada M, Morishita N, Dougan DR, Chen CH, Levin I, Zou H, Kuno M, Arimura N, Kikukawa Y, Kondo M, Tohyama K, Sato K. Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway. J Med Chem. 2023 May 11;66(9):6354-6371. PMID:37120845 doi:10.1021/acs.jmedchem.3c00348