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- PDB-8d95: Scaffold Hopping via Ring Opening Enables Identification of Acycl... -

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Basic information

Entry
Database: PDB / ID: 8d95
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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-QIE / Complement factor D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.166 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 9, 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 1.2Nov 13, 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)25,0102
Polymers24,5971
Non-polymers4131
Water1,00956
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.302, 44.800, 62.132
Angle α, β, γ (deg.)90.000, 114.392, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-447-

HOH

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Components

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


Mass: 24596.965 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK293-E 253 / Gene: CFD, DF, PFD / Cell (production host): Human embryonic / Organ (production host): kidney / Production host: Homo sapiens (human) / References: UniProt: P00746, complement factor D
#2: Chemical ChemComp-QIE / N-(6-bromopyridin-2-yl)-1-[(3-cyanophenyl)acetyl]-L-prolinamide


Mass: 413.268 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17BrN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 1.97 Å3/Da / Density % sol: 37 % / Description: needles
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.8 / Details: PEG 6k / PH range: 6.2

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Data collection

DiffractionMean temperature: 170 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: Apr 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.16→50 Å / Num. obs: 30307 / % possible obs: 97.1 % / Redundancy: 3.4 % / CC1/2: 0.965 / CC star: 0.991 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.039 / Rrim(I) all: 0.079 / Rsym value: 0.071 / Χ2: 0.858 / Net I/σ(I): 3.6
Reflection shellResolution: 2.3→2.32 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.133 / Mean I/σ(I) obs: 20 / Num. unique obs: 815 / CC1/2: 0.965 / CC star: 0.991 / Rpim(I) all: 0.114 / Rsym value: 0.116 / Χ2: 0.657 / % possible all: 84.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
HKL-3000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DIC

1dic


Resolution: 2.166→35.189 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.901 / WRfactor Rfree: 0.265 / WRfactor Rwork: 0.204 / SU B: 6.926 / SU ML: 0.179 / Average fsc free: 0.9507 / Average fsc work: 0.9735 / Cross valid method: FREE R-VALUE / ESU R: 0.463 / ESU R Free: 0.27
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2629 510 5.527 %
Rwork0.2018 8717 -
all0.205 --
obs-9227 89.141 %
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: 30.734 Å2
Baniso -1Baniso -2Baniso -3
1-0.081 Å2-0 Å20.019 Å2
2---0.057 Å2-0 Å2
3----0.029 Å2
Refinement stepCycle: LAST / Resolution: 2.166→35.189 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1687 0 0 56 1743
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0121725
X-RAY DIFFRACTIONr_bond_other_d0.0030.0161582
X-RAY DIFFRACTIONr_angle_refined_deg1.4021.6562347
X-RAY DIFFRACTIONr_angle_other_deg0.7011.5733683
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9955218
X-RAY DIFFRACTIONr_dihedral_angle_2_deg15.2991018
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.68910271
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.2581070
X-RAY DIFFRACTIONr_chiral_restr0.0570.2263
X-RAY DIFFRACTIONr_chiral_restr_other2.1690.24
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021996
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02324
X-RAY DIFFRACTIONr_nbd_refined0.2110.2294
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1990.21449
X-RAY DIFFRACTIONr_nbtor_refined0.1610.2789
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0830.2918
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.260
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0910.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2070.223
X-RAY DIFFRACTIONr_nbd_other0.2030.265
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2670.27
X-RAY DIFFRACTIONr_mcbond_it2.3483.07881
X-RAY DIFFRACTIONr_mcbond_other2.3423.069880
X-RAY DIFFRACTIONr_mcangle_it3.8164.5661094
X-RAY DIFFRACTIONr_mcangle_other3.8144.5741095
X-RAY DIFFRACTIONr_scbond_it2.8113.432844
X-RAY DIFFRACTIONr_scbond_other2.8093.432845
X-RAY DIFFRACTIONr_scangle_it4.1864.9961253
X-RAY DIFFRACTIONr_scangle_other4.1844.9961254
X-RAY DIFFRACTIONr_lrange_it7.58253.5671794
X-RAY DIFFRACTIONr_lrange_other7.57753.6041790
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
2.166-2.2220.46340.1991630.2047790.830.97521.43770.183
2.222-2.2830.387270.2024190.2137140.9090.97562.4650.185
2.283-2.3490.248360.1985920.2017260.9580.97586.50140.18
2.349-2.420.315450.2175920.2246800.950.96993.67650.2
2.42-2.4990.267510.2276100.236910.9550.96895.65850.204
2.499-2.5870.383230.2136240.2196660.8780.97497.14710.2
2.587-2.6840.276440.2325450.2366010.9540.96998.00330.21
2.684-2.7930.296410.2145760.226260.9560.97398.56230.199
2.793-2.9160.226300.2095450.215810.9720.97298.96730.205
2.916-3.0570.297260.2195230.2225570.9480.96998.56370.214
3.057-3.2210.304180.2055100.2095300.9430.97499.62260.199
3.221-3.4150.288210.2084920.2115140.9540.97399.80550.203
3.415-3.6480.296260.1984540.2034800.9440.9761000.199
3.648-3.9370.216280.1863980.1884270.9780.9899.76580.186
3.937-4.3070.236340.1663800.1724170.9720.98399.28060.18
4.307-4.8070.172180.1663540.1673750.9780.98499.20.188
4.807-5.5330.169180.1763210.1753400.9830.98499.70590.199
5.533-6.7350.37490.2262620.2292720.980.97299.63240.244
6.735-9.3560.25280.2142200.2152290.930.97399.56330.237
9.356-35.1890.6430.2681360.2731420.780.94197.88730.317

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