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- PDB-8gmn: Crystal structure of human C1s in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 8gmn
TitleCrystal structure of human C1s in complex with inhibitor
ComponentsComplement C1s subcomponent
KeywordsHYDROLASE/INHIBITOR / Complement C1s Hydrolase. Protease Serine protease / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


complement subcomponent C_overbar_1s_ / Classical antibody-mediated complement activation / Initial triggering of complement / complement activation, classical pathway / Regulation of Complement cascade / blood microparticle / serine-type endopeptidase activity / innate immune response / calcium ion binding / proteolysis ...complement subcomponent C_overbar_1s_ / Classical antibody-mediated complement activation / Initial triggering of complement / complement activation, classical pathway / Regulation of Complement cascade / blood microparticle / serine-type endopeptidase activity / innate immune response / calcium ion binding / proteolysis / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Peptidase S1A, complement C1r/C1S/mannan-binding / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. ...Peptidase S1A, complement C1r/C1S/mannan-binding / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Coagulation Factor Xa inhibitory site / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-ZWK / Complement C1s subcomponent
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsDougan, D.R. / Lane, W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.
Authors: Ikeda, Z. / Kamei, T. / Sasaki, Y. / Reynolds, M. / Sakai, N. / Yoshikawa, M. / Tawada, M. / Morishita, N. / Dougan, D.R. / Chen, C.H. / Levin, I. / Zou, H. / Kuno, M. / Arimura, N. / ...Authors: Ikeda, Z. / Kamei, T. / Sasaki, Y. / Reynolds, M. / Sakai, N. / Yoshikawa, M. / Tawada, M. / Morishita, N. / Dougan, D.R. / Chen, C.H. / Levin, I. / Zou, H. / Kuno, M. / Arimura, N. / Kikukawa, Y. / Kondo, M. / Tohyama, K. / Sato, K.
History
DepositionMar 26, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 2.0May 24, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / citation / citation_author / database_PDB_caveat / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_residues
Item: _atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id ..._atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _database_PDB_caveat.text / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.auth_seq_num / _pdbx_poly_seq_scheme.pdb_ins_code / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_unobs_or_zero_occ_residues.PDB_ins_code / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _pdbx_unobs_or_zero_occ_residues.label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Complement C1s subcomponent
B: Complement C1s subcomponent
C: Complement C1s subcomponent
D: Complement C1s subcomponent
hetero molecules


Theoretical massNumber of molelcules
Total (without water)164,67510
Polymers163,0934
Non-polymers1,5826
Water4,306239
1
A: Complement C1s subcomponent
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1212
Polymers40,7731
Non-polymers3471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Complement C1s subcomponent
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2173
Polymers40,7731
Non-polymers4432
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Complement C1s subcomponent
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2173
Polymers40,7731
Non-polymers4432
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Complement C1s subcomponent
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1212
Polymers40,7731
Non-polymers3471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.471, 77.647, 108.484
Angle α, β, γ (deg.)86.13, 79.09, 71.08
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Complement C1s subcomponent / C1 esterase / Complement component 1 subcomponent s


Mass: 40773.234 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C1S / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P09871, complement subcomponent C_overbar_1s_
#2: Chemical
ChemComp-ZWK / [4-(1-aminophthalazin-6-yl)piperazin-1-yl](2-methylphenyl)methanone


Mass: 347.414 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H21N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 239 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.61 Å3/Da / Density % sol: 52.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 22% PEG 3350, 50-100 mM Ammonium Sulphate and 100 mM TRIS pH 7.5-8.0
PH range: 7.5-8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.51→46.99 Å / Num. obs: 47284 / % possible obs: 90.5 % / Redundancy: 1.9 % / CC1/2: 0.989 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.106 / Rrim(I) all: 0.15 / Χ2: 0.96 / Net I/σ(I): 5.9 / Num. measured all: 91592
Reflection shellResolution: 2.51→2.59 Å / % possible obs: 56.1 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.928 / Num. measured all: 4921 / Num. unique obs: 2687 / CC1/2: 0.322 / Rpim(I) all: 0.928 / Rrim(I) all: 1.313 / Χ2: 0.95 / Net I/σ(I) obs: 0.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
Aimlessdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→35 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.86 / SU B: 31.697 / SU ML: 0.32 / Cross valid method: THROUGHOUT / ESU R: 0.664 / ESU R Free: 0.345 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.28141 2196 5 %RANDOM
Rwork0.22428 ---
obs0.22714 42122 94.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 50.25 Å2
Baniso -1Baniso -2Baniso -3
1--1.6 Å20.83 Å2-0.63 Å2
2--0.98 Å20.38 Å2
3---0.63 Å2
Refinement stepCycle: 1 / Resolution: 2.6→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8362 0 114 239 8715
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0128713
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4571.66211823
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg10.6215.0381054
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.07122.634410
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.667151395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2191545
X-RAY DIFFRACTIONr_chiral_restr0.1040.21080
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026850
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.0863.1464281
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.934.6865304
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.6743.4424432
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.91341.26113010
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.437 125 -
Rwork0.378 2290 -
obs--69.2 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.11210.20160.00460.54360.24920.36280.02140.00340.00570.09710.0027-0.0388-0.06060.0035-0.02410.1462-0.0191-0.0920.0309-0.05220.28628.46427.656.572
20.9703-0.3404-0.13080.74570.18490.4585-0.00420.0249-0.0175-0.04230.043-0.04310.0392-0.0164-0.03880.1469-0.04650.0130.0315-0.06450.254933.23260.1442.231
31.51820.33170.06270.4218-0.12411.31020.01320.4696-0.19630.07240.1422-0.0241-0.1167-0.0662-0.15530.08-0.0258-0.03710.2806-0.10570.1663-3.25110.415-28.54
41.6257-0.26580.45450.2505-0.31441.413-0.1485-0.68670.2873-0.12530.1897-0.08110.112-0.2182-0.04130.12630.0188-0.00980.3612-0.17490.1241-2.4862.94636.889
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A364 - 682
2X-RAY DIFFRACTION1A700
3X-RAY DIFFRACTION1C701
4X-RAY DIFFRACTION2B365 - 683
5X-RAY DIFFRACTION2B701 - 702
6X-RAY DIFFRACTION3C365 - 684
7X-RAY DIFFRACTION3C702
8X-RAY DIFFRACTION4D365 - 684
9X-RAY DIFFRACTION4D700

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