8GMN: Human C1s

Crystal structure of human C1s in complex with inhibitor. Determined by X-ray diffraction at 2.6 Å resolution. Released 17 May 2023.

Method: X-ray diffraction
Resolution: 2.6 Å
Organism: Homo sapiens
Chains: 4
Atoms: 8,721
Mol. weight: 164.67 kDa
Ligands: ZWK
Released: 17 May 2023

Explore 8GMN in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

8GMN contains 47 α-helices and 94 β-strands across 4 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.

Chain A: 10 helices, 25 β-strands

Element	Residues	Length	Sheet
β-strand	368	1	1
β-strand	386	1	1
β-strand	391-393	3	2
β-strand	421-423	3	2
β-strand	439	1	3
β-strand	442-443	2	4
α-helix	446-448	3
β-strand	452-455	4	5
β-strand	460-466	7	5
β-strand	469-472	4	5
α-helix	474-477	4
β-strand	485-486	2	5
β-strand	491	1	6
α-helix	495-497	3
β-strand	502-503	2	5
β-strand	505-510	6	5
β-strand	531-535	5	5
α-helix	538-541	4
β-strand	542	1	7
β-strand	545	1	7
β-strand	549	1	4
α-helix	550-552	3
α-helix	555-557	3
β-strand	564-569	6	4
β-strand	581	1	6
β-strand	583-590	8	4
α-helix	592-596	5
α-helix	609-611	3
β-strand	616-619	4	4
β-strand	626	1	3
β-strand	635-640	6	4
β-strand	643-655	13	4
β-strand	663-667	5	4
α-helix	668-671	4
α-helix	672-680	9

Chain B: 12 helices, 23 β-strands

Element	Residues	Length	Sheet
β-strand	391-393	3	8
β-strand	421-423	3	8
β-strand	439	1	9
β-strand	442-443	2	10
α-helix	446-448	3
β-strand	452-455	4	11
β-strand	460-466	7	11
β-strand	469-472	4	11
α-helix	474-477	4
β-strand	485-487	3	11
β-strand	491	1	12
α-helix	494-497	4
β-strand	501-503	3	11
α-helix	504	1
β-strand	505-510	6	11
β-strand	531-535	5	11
α-helix	538-541	4
β-strand	542	1	13
β-strand	545	1	13
α-helix	547-548	2
β-strand	549	1	10
α-helix	550-552	3
α-helix	555-557	3
β-strand	564-569	6	10
β-strand	581	1	12
β-strand	583-590	8	10
α-helix	593-596	4
α-helix	609-611	3
β-strand	616-620	5	10
β-strand	626	1	9
β-strand	635-640	6	10
β-strand	643-655	13	10
β-strand	662-667	6	10
α-helix	668-671	4
α-helix	672-680	9

Chain C: 13 helices, 23 β-strands

Element	Residues	Length	Sheet
β-strand	391	1	14
β-strand	423	1	14
α-helix	424-425	2
β-strand	439	1	15
β-strand	442-443	2	16
α-helix	446-448	3
β-strand	452-455	4	17
β-strand	460-466	7	17
β-strand	469-472	4	17
α-helix	474-477	4
β-strand	485-486	2	17
β-strand	491	1	18
β-strand	502-503	2	17
β-strand	505-510	6	17
α-helix	515-516	2
α-helix	520-522	3
β-strand	531-535	5	17
α-helix	538-541	4
β-strand	542	1	19
β-strand	545	1	19
α-helix	547-548	2
β-strand	549	1	16
α-helix	555-557	3
β-strand	564-569	6	16
β-strand	581	1	18
β-strand	583-589	7	16
α-helix	592-597	6
α-helix	609-611	3
β-strand	616-620	5	16
α-helix	622-624	3
β-strand	626	1	15
β-strand	635-640	6	16
β-strand	643-655	13	16
β-strand	662-667	6	16
α-helix	668-671	4
α-helix	672-680	9

Chain D: 12 helices, 23 β-strands

Element	Residues	Length	Sheet
β-strand	391-393	3	20
β-strand	421-423	3	20
β-strand	439	1	21
β-strand	442-443	2	22
α-helix	446-448	3
β-strand	452-455	4	23
β-strand	460-464	5	23
β-strand	469-472	4	23
α-helix	474-478	5
β-strand	485-486	2	23
β-strand	491	1	24
β-strand	502-503	2	23
α-helix	504	1
β-strand	505-510	6	23
α-helix	520-522	3
β-strand	531-535	5	23
α-helix	538-541	4
β-strand	542	1	25
β-strand	545	1	25
α-helix	547-548	2
β-strand	549	1	22
α-helix	555-557	3
β-strand	564-569	6	22
β-strand	581	1	24
β-strand	583-590	8	22
α-helix	592-597	6
α-helix	609-611	3
β-strand	616-620	5	22
α-helix	622-624	3
β-strand	626	1	21
β-strand	635-640	6	22
β-strand	643-655	13	22
β-strand	662-667	6	22
α-helix	668-671	4
α-helix	672-680	9

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Complement C1s subcomponent	A, B, C, D	protein	371	Homo sapiens	P09871 (AlphaFold model)

Sequence of entity 1 (A, B, C, D), FASTA

>8GMN_1 Complement C1s subcomponent (chains A, B, C, D)
MLLVNQSHQGFNKEHTSKMVSAIVLYVLLAAAAHSAFADLDCGIPESIENGKVEDPESTL
FGSVIRYTCEEPYYYMENGGGGEYHCAGNGSWVNEVLGPELPKCVPVCGVPREPFEEKQR
IIGGSDADIKNFPWQVFFDNPWAGGALINEYWVLTAAHVVEGNREPTMYVGSTSVQTSRL
AKSKMLTPEHVFIHPGWKLLAVPEGRTNFDNDIALVRLKDPVKMGPTVSPICLPGTSSDY
NLMDGDLGLISGWGRTEKRDRAVRLKAARLPVAPLRKCKEVKVEKPTADAEAYVFTPNMI
CAGGEKGMDSCKGDSGGAFAVQDPNDKTKFYAAGLVSWGPQCGTYGLYTRVKNYVDWIMK
TMQENSTPRED

Ligands and cofactors

ID	Name	Formula	Copies
ZWK	[4-(1-aminophthalazin-6-yl)piperazin-1-yl](2-methylphenyl)methanone	C20 H21 N5 O	4

Water and common crystallization additives (SO4) are not listed.

Primary citation

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. et al. J Med Chem (2023) 66:6354-6371. DOI 10.1021/acs.jmedchem.3c00348 · PubMed

Other PDB entries of the same protein (UniProt P09871 (AlphaFold model), which also has an AlphaFold model), best resolution first:

1NZI 1.5 Å, Crystal Structure of the CUB1-EGF Interaction Domain of Complement Protease C1s
1ELV 1.7 Å, Crystal structure of the catalytic domain of human complement C1S protease
8TYP 1.8 Å, Complement Protease C1s Inhibited by 6-(4-phenylpiperazin-1-yl)pyridine-3-carboximidamide
4LOS 2.0 Å, C1s CUB2-CCP1
4LOR 2.5 Å, C1s CUB1-EGF-CUB2 in complex with a collagen-like peptide from C1q
5UBM 2.5 Å, Crystal structure of human C1s in complex with inhibitor gigastasin
9X1H 2.6 Å, Cryo-EM Structure of human complement C1s CUB domain in complex with RAY121
4J1Y 2.66 Å, The X-ray crystal structure of human complement protease C1s zymogen
4LOT 2.92 Å, C1s CUB2-CCP1-CCP2
4LMF 2.92 Å, C1s CUB1-egf-CUB2
8W18 3.94 Å, The crystal structure of the Michaelis-Menten complex of a C1s/C1-INH at 3.94 Angstroms
6F1C 4.2 Å, C1rC1s complex

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