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- PDB-7n7x: Crystal structure of BCX7353(ORLADEYO) in complex with human plas... -

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Basic information

Entry
Database: PDB / ID: 7n7x
TitleCrystal structure of BCX7353(ORLADEYO) in complex with human plasma kallikrein serine protease domain at 2.1 angstrom resolution
ComponentsPlasma kallikrein light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / kallikrein / blood / plasma / plasma kallikrein-mediated edema / acute hereditary angioedema / HAE / HMWK / hereditary angioedema / HAW / bradykinin / fletcher factor / kininogenin / serine protease / edema / orladeyo / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


plasma kallikrein / Factor XII activation / Defective SERPING1 causes hereditary angioedema / positive regulation of fibrinolysis / zymogen activation / plasminogen activation / Defective factor XII causes hereditary angioedema / Activation of Matrix Metalloproteinases / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation ...plasma kallikrein / Factor XII activation / Defective SERPING1 causes hereditary angioedema / positive regulation of fibrinolysis / zymogen activation / plasminogen activation / Defective factor XII causes hereditary angioedema / Activation of Matrix Metalloproteinases / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. ...Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / 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
Orladeyo / PHOSPHATE ION / Plasma kallikrein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.097 Å
AuthorsKrishnan, R. / Yarlagadda, B.S. / Kotian, P. / Polach, K.J. / Zhang, W.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).
Authors: Kotian, P.L. / Wu, M. / Vadlakonda, S. / Chintareddy, V. / Lu, P. / Juarez, L. / Kellogg-Yelder, D. / Chen, X. / Muppa, S. / Chambers-Wilson, R. / Davis Parker, C. / Williams, J. / Polach, K. ...Authors: Kotian, P.L. / Wu, M. / Vadlakonda, S. / Chintareddy, V. / Lu, P. / Juarez, L. / Kellogg-Yelder, D. / Chen, X. / Muppa, S. / Chambers-Wilson, R. / Davis Parker, C. / Williams, J. / Polach, K.J. / Zhang, W. / Raman, K. / Babu, Y.S.
History
DepositionJun 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 22, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Plasma kallikrein light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,3273
Polymers26,6691
Non-polymers6582
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.726, 59.752, 79.023
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Plasma kallikrein light chain /


Mass: 26669.365 Da / Num. of mol.: 1 / Fragment: Peptidase S1 domain / Mutation: N6E, N63E, N104E, C113S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KLKB1, KLK3 / Cell line (production host): Sf9 / Production host: unidentified baculovirus / References: UniProt: P03952
#2: Chemical ChemComp-0RI / Orladeyo / 1-[3-(aminomethyl)phenyl]-N-(5-{(R)-[3-(aminomethyl)phenyl][(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide / Berotralstat


Mass: 562.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H26F4N6O / Comment: medication*YM
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.48 Å3/Da / Density % sol: 50 % / Description: cuboids
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 25% PEG 6000, 0.1MES buffer

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: x-stream / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.518 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Sep 27, 2017 / Details: osmic mirrors
RadiationMonochromator: osmic mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.518 Å / Relative weight: 1
ReflectionResolution: 2.09→40.39 Å / Num. obs: 15531 / % possible obs: 97.6 % / Observed criterion σ(F): 3 / Redundancy: 3.9 % / Biso Wilson estimate: 23.7 Å2 / CC1/2: 0.963 / CC star: 0.99 / Rpim(I) all: 0.031 / Rrim(I) all: 0.069 / Χ2: 3.289 / Net I/σ(I): 37.7
Reflection shellResolution: 2.09→2.16 Å / Redundancy: 2 % / Mean I/σ(I) obs: 9 / Num. unique obs: 1318 / CC1/2: 0.963 / CC star: 0.99 / Rpim(I) all: 0.108 / Rrim(I) all: 0.169 / Χ2: 2.224 / % possible all: 85

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ANY

2any


Resolution: 2.097→40.39 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.891 / SU B: 4.885 / SU ML: 0.132 / Cross valid method: FREE R-VALUE / σ(F): 3 / ESU R: 0.228 / ESU R Free: 0.203
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2592 769 4.97 %
Rwork0.1991 14703 -
all0.202 --
obs-15472 98.21 %
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: 25.053 Å2
Baniso -1Baniso -2Baniso -3
1--0.001 Å2-0 Å2-0 Å2
2---0 Å20 Å2
3---0.001 Å2
Refinement stepCycle: LAST / Resolution: 2.097→40.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1828 0 46 87 1961
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0131927
X-RAY DIFFRACTIONr_bond_other_d0.0030.0181785
X-RAY DIFFRACTIONr_angle_refined_deg1.6231.6682619
X-RAY DIFFRACTIONr_angle_other_deg1.3621.6084121
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4245227
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.88523.73691
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.91315328
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.985157
X-RAY DIFFRACTIONr_chiral_restr0.0750.2241
X-RAY DIFFRACTIONr_chiral_restr_other1.6470.26
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022154
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02440
X-RAY DIFFRACTIONr_nbd_refined0.2090.2365
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.21702
X-RAY DIFFRACTIONr_nbtor_refined0.1720.2889
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0770.2888
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.286
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1820.219
X-RAY DIFFRACTIONr_nbd_other0.1960.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1540.28
X-RAY DIFFRACTIONr_mcbond_it2.4862.4915
X-RAY DIFFRACTIONr_mcbond_other2.462.395913
X-RAY DIFFRACTIONr_mcangle_it4.0563.5811139
X-RAY DIFFRACTIONr_mcangle_other4.063.5861140
X-RAY DIFFRACTIONr_scbond_it2.7722.7911012
X-RAY DIFFRACTIONr_scbond_other2.7632.7861009
X-RAY DIFFRACTIONr_scangle_it4.5044.0481477
X-RAY DIFFRACTIONr_scangle_other4.4964.0391472
X-RAY DIFFRACTIONr_lrange_it6.73228.0742176
X-RAY DIFFRACTIONr_lrange_other6.71627.9942167
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.097-2.1510.31500.19974X-RAY DIFFRACTION90.7801
2.151-2.210.288560.2081014X-RAY DIFFRACTION95.4505
2.21-2.2740.244560.203985X-RAY DIFFRACTION96.7472
2.274-2.3440.3550.195970X-RAY DIFFRACTION97.5262
2.344-2.420.233480.18948X-RAY DIFFRACTION98.0315
2.42-2.5050.276390.195963X-RAY DIFFRACTION99.1098
2.505-2.5990.268410.214909X-RAY DIFFRACTION99.1649
2.599-2.7050.3460.223866X-RAY DIFFRACTION99.8905
2.705-2.8250.28480.217850X-RAY DIFFRACTION99.7778
2.825-2.9620.277360.214790X-RAY DIFFRACTION99.6381
2.962-3.1220.298430.236785X-RAY DIFFRACTION99.759
3.122-3.310.268260.204735X-RAY DIFFRACTION99.6073
3.31-3.5380.188310.187700X-RAY DIFFRACTION99.5913
3.538-3.8190.212310.185643X-RAY DIFFRACTION99.8519
3.819-4.1810.225360.17598X-RAY DIFFRACTION99.8425
4.181-4.670.202350.163537X-RAY DIFFRACTION99.4783
4.67-5.3840.259340.182477X-RAY DIFFRACTION99.6101
5.384-6.5730.297280.224418X-RAY DIFFRACTION100
6.573-9.2090.341190.201335X-RAY DIFFRACTION100
8-40.390.358110.284206X-RAY DIFFRACTION96.4444

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