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Entry
Database: PDB / ID: 6rav
TitleComplement factor B protease domain in complex with the reversible inhibitor 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid
ComponentsComplement factor B
KeywordsHYDROLASE / Complement / immune / inhibitor / c3 convertase
Function / homology
Function and homology information


alternative-complement-pathway C3/C5 convertase / complement binding / Alternative complement activation / Activation of C3 and C5 / complement activation / complement activation, alternative pathway / Regulation of Complement cascade / response to bacterium / blood microparticle / serine-type endopeptidase activity ...alternative-complement-pathway C3/C5 convertase / complement binding / Alternative complement activation / Activation of C3 and C5 / complement activation / complement activation, alternative pathway / Regulation of Complement cascade / response to bacterium / blood microparticle / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Complement factor B / Complement B/C2 / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / von Willebrand factor type A domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / von Willebrand factor (vWF) type A domain / VWFA domain profile. ...Complement factor B / Complement B/C2 / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / von Willebrand factor type A domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / von Willebrand factor (vWF) type A domain / VWFA domain profile. / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-JGQ / Complement factor B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsAdams, C.M. / Sellner, H. / Ehara, T. / Mac Sweeney, A. / Crowley, M. / Anderson, K. / Karki, R. / Mainolfi, N. / Valeur, E. / Sirockin, F. ...Adams, C.M. / Sellner, H. / Ehara, T. / Mac Sweeney, A. / Crowley, M. / Anderson, K. / Karki, R. / Mainolfi, N. / Valeur, E. / Sirockin, F. / Gerhartz, B. / Erbel, P. / Hughes, N. / Smith, T.M. / Cumin, F. / Argikar, U. / Mogi, M. / Sedrani, R. / Wiesmann, C. / Jaffee, B. / Maibaum, J. / Flohr, S. / Harrison, R. / Eder, J.
Citation
Journal: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.
Authors: Schubart, A. / Anderson, K. / Mainolfi, N. / Sellner, H. / Ehara, T. / Adams, C.M. / Mac Sweeney, A. / Liao, S.M. / Crowley, M. / Littlewood-Evans, A. / Sarret, S. / Wieczorek, G. / Perrot, ...Authors: Schubart, A. / Anderson, K. / Mainolfi, N. / Sellner, H. / Ehara, T. / Adams, C.M. / Mac Sweeney, A. / Liao, S.M. / Crowley, M. / Littlewood-Evans, A. / Sarret, S. / Wieczorek, G. / Perrot, L. / Dubost, V. / Flandre, T. / Zhang, Y. / Smith, R.J.H. / Risitano, A.M. / Karki, R.G. / Zhang, C. / Valeur, E. / Sirockin, F. / Gerhartz, B. / Erbel, P. / Hughes, N. / Smith, T.M. / Cumin, F. / Argikar, U.A. / Haraldsson, B. / Mogi, M. / Sedrani, R. / Wiesmann, C. / Jaffee, B. / Maibaum, J. / Flohr, S. / Harrison, R. / Eder, J.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.
Authors: Schubart, A. / Anderson, K. / Mainolfi, N. / Sellner, H. / Ehara, T. / Adams, C.M. / Mac Sweeney, A. / Liao, S.M. / Crowley, M. / Littlewood-Evans, A. / Sarret, S. / Wieczorek, G. / Perrot, ...Authors: Schubart, A. / Anderson, K. / Mainolfi, N. / Sellner, H. / Ehara, T. / Adams, C.M. / Mac Sweeney, A. / Liao, S.M. / Crowley, M. / Littlewood-Evans, A. / Sarret, S. / Wieczorek, G. / Perrot, L. / Dubost, V. / Flandre, T. / Zhang, Y. / Smith, R.J.H. / Risitano, A.M. / Karki, R.G. / Zhang, C. / Valeur, E. / Sirockin, F. / Gerhartz, B. / Erbel, P. / Hughes, N. / Smith, T.M. / Cumin, F. / Argikar, U.A. / Haraldsson, B. / Mogi, M. / Sedrani, R. / Wiesmann, C. / Jaffee, B. / Maibaum, J. / Flohr, S. / Harrison, R. / Eder, J.
History
DepositionApr 8, 2019Deposition site: PDBE / Processing site: PDBE
SupersessionApr 17, 2019ID: 6QSV
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.country / _citation.id ..._citation.country / _citation.id / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.citation_id / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 14, 2019Group: Data collection / Structure summary / Category: pdbx_poly_seq_scheme / Item: _pdbx_poly_seq_scheme.auth_seq_num
Revision 1.3Sep 18, 2019Group: Data collection / Refinement description / Structure summary
Category: pdbx_poly_seq_scheme / struct_ncs_dom / Item: _pdbx_poly_seq_scheme.auth_seq_num
Revision 1.4Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.5Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry
Revision 1.6Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Complement factor B
BBB: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,36811
Polymers65,9122
Non-polymers1,4569
Water6,593366
1
AAA: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5714
Polymers32,9561
Non-polymers6153
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7977
Polymers32,9561
Non-polymers8426
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.463, 97.446, 61.815
Angle α, β, γ (deg.)90.000, 100.475, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Complement factor B / C3/C5 convertase / Glycine-rich beta glycoprotein / GBG / PBF2 / Properdin factor B


Mass: 32955.883 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFB, BF, BFD / Production host: Drosophila melanogaster (fruit fly)
References: UniProt: P00751, alternative-complement-pathway C3/C5 convertase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-JGQ / 4-[(2~{S},4~{S})-4-ethoxy-1-[(5-methoxy-7-methyl-1~{H}-indol-4-yl)methyl]piperidin-2-yl]benzoic acid


Mass: 422.517 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H30N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 366 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.54 Å3/Da / Density % sol: 51.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 24 % (w/v) PEG3350, 0.2 M ammonium acetate, 0.1 M Bis-Tris (pH 5.5), 2mM inhibitor

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 1, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→48.723 Å / Num. obs: 68802 / % possible obs: 98.8 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Rmerge(I) obs: 0.068 / Rrim(I) all: 0.081 / Net I/σ(I): 10.82
Reflection shellResolution: 1.7→1.77 Å / Redundancy: 3.15 % / Rmerge(I) obs: 0.814 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 7743 / Rrim(I) all: 0.991 / % possible all: 96.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0238 2018/15/10refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1dle

1dle


Resolution: 1.7→48.723 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.945 / SU B: 3.89 / SU ML: 0.113 / Cross valid method: FREE R-VALUE / ESU R: 0.112 / ESU R Free: 0.108
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2267 3435 -
Rwork0.1952 --
all0.197 --
obs-68598 98.491 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 31.753 Å2
Baniso -1Baniso -2Baniso -3
1-2.501 Å20 Å24.074 Å2
2---0.945 Å20 Å2
3----2.867 Å2
Refinement stepCycle: LAST / Resolution: 1.7→48.723 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4409 0 89 366 4864
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134674
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174261
X-RAY DIFFRACTIONr_angle_refined_deg1.5571.6676361
X-RAY DIFFRACTIONr_angle_other_deg1.3221.589927
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8265577
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.26322.696230
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.20815794
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2731526
X-RAY DIFFRACTIONr_chiral_restr0.0760.2594
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025167
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02927
X-RAY DIFFRACTIONr_nbd_refined0.1910.2831
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.24075
X-RAY DIFFRACTIONr_nbtor_refined0.1660.22166
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.22126
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1450.2339
X-RAY DIFFRACTIONr_metal_ion_refined0.0370.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1840.225
X-RAY DIFFRACTIONr_nbd_other0.1880.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2310.215
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0630.22
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0690.22
X-RAY DIFFRACTIONr_mcbond_it2.5443.1322269
X-RAY DIFFRACTIONr_mcbond_other2.5433.1322268
X-RAY DIFFRACTIONr_mcangle_it3.7154.6852835
X-RAY DIFFRACTIONr_mcangle_other3.7154.6852836
X-RAY DIFFRACTIONr_scbond_it3.4953.5682405
X-RAY DIFFRACTIONr_scbond_other3.3933.5492317
X-RAY DIFFRACTIONr_scangle_it5.275.1863518
X-RAY DIFFRACTIONr_scangle_other5.1195.153392
X-RAY DIFFRACTIONr_lrange_it6.93437.2025159
X-RAY DIFFRACTIONr_lrange_other6.84537.1224963
X-RAY DIFFRACTIONr_ncsr_local_group_10.0960.058512
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)WRfactor Rwork
1.7-1.7440.3722380.3434433513990.89320.325
1.744-1.7920.3272480.2934706496999.69810.265
1.792-1.8440.2482410.2854576484499.44260.256
1.844-1.90.2352340.2474454473599.00740.217
1.9-1.9630.3192280.294321460598.78390.265
1.963-2.0310.2292200.2064189442399.68350.182
2.031-2.1080.2452120.2064020426799.17970.181
2.108-2.1940.2422060.1913915412899.83040.168
2.194-2.2910.2461920.2463656395697.270.224
2.291-2.4030.2271880.1723576377599.70860.156
2.403-2.5320.2181780.1673381356799.77570.155
2.532-2.6860.2351710.1733251344899.24590.165
2.686-2.870.211600.1713032320699.56330.169
2.87-3.10.2371470.1762801297599.09240.18
3.1-3.3940.2051350.1782563275797.860.185
3.394-3.7920.2211220.1782309246998.46090.188
3.792-4.3750.1691080.1522056220698.09610.174
4.375-5.3470.195930.1491762187299.09190.177
5.347-7.5170.193720.1751375146498.83880.206
7.517-48.7230.188420.20478683599.16170.244

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