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- PDB-8dg6: Scaffold Hopping via Ring Opening Enables Identification of Acycl... -

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Basic information

Entry
Database: PDB / ID: 8dg6
TitleScaffold Hopping via Ring Opening Enables Identification of Acyclic Compounds as New Complement Factor D Inhibitors
ComponentsComplement factor D
KeywordsHYDROLASE/HYDROLASE INHIBITOR / serine protease inhibitor complex / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


complement factor D / Alternative complement activation / complement activation / complement activation, alternative pathway / serine-type peptidase activity / platelet alpha granule lumen / protein maturation / response to bacterium / Platelet degranulation / secretory granule lumen ...complement factor D / Alternative complement activation / complement activation / complement activation, alternative pathway / serine-type peptidase activity / platelet alpha granule lumen / protein maturation / response to bacterium / Platelet degranulation / secretory granule lumen / ficolin-1-rich granule lumen / serine-type endopeptidase activity / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
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 / Trypsin-like serine proteases ...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 / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-S7X / Complement factor D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.986 Å
AuthorsRaman, K. / Babu, Y.S.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Scaffold hopping via ring opening enables identification of acyclic compounds as new complement Factor D inhibitors.
Authors: Zhang, W. / Wu, M. / Vadlakonda, S. / Juarez, L. / Cheng, X. / Muppa, S. / Chintareddy, V. / Vogeti, L. / Kellogg-Yelder, D. / Williams, J. / Polach, K. / Chen, X. / Raman, K. / Babu, Y.S. / Kotian, P.
History
DepositionJun 23, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,8972
Polymers24,4391
Non-polymers4581
Water1,56787
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: none
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.507, 44.955, 63.417
Angle α, β, γ (deg.)90.000, 117.312, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Complement factor D / Adipsin / C3 convertase activator / Properdin factor D


Mass: 24438.807 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFD, DF, PFD / Cell line (production host): HEK293 / Organ (production host): kidney / Production host: Homo sapiens (human) / Tissue (production host): embroyonic / References: UniProt: P00746, complement factor D
#2: Chemical ChemComp-S7X / 1-{2-[(2S)-2-{[(3-chloro-2-fluorophenyl)methyl]carbamoyl}pyrrolidin-1-yl]-2-oxoethyl}-1H-indazole-3-carboxamide


Mass: 457.885 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21ClFN5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.08 Å3/Da / Density % sol: 40.93 % / Description: rods
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.8 / Details: peg4k 20-30% / PH range: 5.8-6.4

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Data collection

DiffractionMean temperature: 150 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Nov 4, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.98→50 Å / Num. obs: 12847 / % possible obs: 98.3 % / Redundancy: 3.7 % / CC1/2: 0.916 / CC star: 0.978 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.044 / Rsym value: 0.087 / Χ2: 0.937 / Net I/σ(I): 14
Reflection shellResolution: 1.98→2.05 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 3 / Num. unique obs: 1138 / CC1/2: 0.916 / CC star: 0.978 / Rpim(I) all: 0.16 / % possible all: 87.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0350refinement
HKL-3000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1dic

1dic


Resolution: 1.986→37.218 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.903 / SU B: 4.593 / SU ML: 0.131 / Cross valid method: FREE R-VALUE / ESU R: 0.228 / ESU R Free: 0.192
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2512 662 5.167 %
Rwork0.1974 12149 -
all0.2 --
obs-12811 98.199 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 25.135 Å2
Baniso -1Baniso -2Baniso -3
1-0.027 Å2-0 Å2-0.02 Å2
2--0.06 Å2-0 Å2
3----0.044 Å2
Refinement stepCycle: LAST / Resolution: 1.986→37.218 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1595 0 32 87 1714
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0121664
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161521
X-RAY DIFFRACTIONr_angle_refined_deg1.4281.6322269
X-RAY DIFFRACTIONr_angle_other_deg0.4851.5543540
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.975208
X-RAY DIFFRACTIONr_dihedral_angle_2_deg16.3869.47419
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.7710257
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.3591067
X-RAY DIFFRACTIONr_chiral_restr0.0630.2253
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021930
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02309
X-RAY DIFFRACTIONr_nbd_refined0.2180.2317
X-RAY DIFFRACTIONr_symmetry_nbd_other0.20.21465
X-RAY DIFFRACTIONr_nbtor_refined0.1690.2789
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.2929
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.283
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1520.218
X-RAY DIFFRACTIONr_nbd_other0.2120.283
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1890.26
X-RAY DIFFRACTIONr_mcbond_it1.9622.476844
X-RAY DIFFRACTIONr_mcbond_other1.962.476844
X-RAY DIFFRACTIONr_mcangle_it2.7943.6981048
X-RAY DIFFRACTIONr_mcangle_other2.7943.6991049
X-RAY DIFFRACTIONr_scbond_it2.8952.865820
X-RAY DIFFRACTIONr_scbond_other2.8942.865821
X-RAY DIFFRACTIONr_scangle_it4.4124.1421221
X-RAY DIFFRACTIONr_scangle_other4.414.1411222
X-RAY DIFFRACTIONr_lrange_it6.4435.0631804
X-RAY DIFFRACTIONr_lrange_other6.41835.0291796
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.986-2.0370.268420.1957750.1989530.9550.97785.72930.171
2.037-2.0930.276610.2088170.2139190.9520.97395.53860.188
2.093-2.1530.278400.2248570.2269180.9560.96897.71240.205
2.153-2.2190.291490.2028020.2078590.9540.97499.06870.185
2.219-2.2920.212370.1818310.1838740.9730.9899.31350.17
2.292-2.3720.271380.1947810.1978240.9530.97799.39320.178
2.372-2.4610.289360.2157450.2187820.9550.97299.87210.203
2.461-2.5610.236360.2067500.2087870.9650.97499.87290.195
2.561-2.6740.306320.1976950.2017300.9520.97799.5890.191
2.674-2.8040.213450.1946530.1957000.9740.97899.71430.186
2.804-2.9550.279300.2096390.2126710.9430.97399.70190.207
2.955-3.1330.254360.2276090.2296460.9520.96899.84520.23
3.133-3.3470.287350.2225710.2266100.9440.9799.34430.233
3.347-3.6130.251330.2155120.2175450.9640.9711000.221
3.613-3.9540.236180.1845060.1855240.9660.9791000.204
3.954-4.4150.257300.1644380.1694690.970.98399.78680.186
4.415-5.0860.241120.1594030.1624150.9710.9861000.183
5.086-6.20.265190.1963430.1993630.9770.9899.72450.219
6.2-8.6490.192240.1992580.1982820.9730.9811000.223
8.649-37.2180.13290.1971640.1941740.9710.96799.42530.232

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