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- PDB-10kz: N-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lea... -

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Basic information

Entry
Database: PDB / ID: 10kz
TitleN-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors
ComponentsPlasma kallikrein
KeywordsHYDROLASE/INHIBITOR / 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 / : ...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 / : / serine-type peptidase activity / blood coagulation / serine-type endopeptidase activity / proteolysis / : / 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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family ...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 / 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
: / Plasma kallikrein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsMerchant, R.R. / Chernyak, N. / Lopez, J.A. / Sharp, P.P. / Mandal, M. / He, J. / Hruza, A. / Rearden, P. / Tatosian, D.A. / Lin, K. ...Merchant, R.R. / Chernyak, N. / Lopez, J.A. / Sharp, P.P. / Mandal, M. / He, J. / Hruza, A. / Rearden, P. / Tatosian, D.A. / Lin, K. / Esmay, J. / Yang, S. / Cheng, A. / Ellsworth, K. / Piou, T. / Fier, P. / Hicks, J. / Sinz, C. / Ogawa, A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2026
Title: N ‐Alkyl and N ‐Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors.
Authors: Merchant, R.R. / Chernyak, N. / Lopez, J.A. / Sharp, P.P. / Mandal, M. / He, J. / Hruza, A. / Rearden, P. / Tatosian, D.A. / Esmay, J. / Yang, S. / Cheng, A.C. / Ellsworth, K. / Ogawa, A. / ...Authors: Merchant, R.R. / Chernyak, N. / Lopez, J.A. / Sharp, P.P. / Mandal, M. / He, J. / Hruza, A. / Rearden, P. / Tatosian, D.A. / Esmay, J. / Yang, S. / Cheng, A.C. / Ellsworth, K. / Ogawa, A. / Piou, T. / Fier, P. / Hicks, J. / Sinz, C. / Ogawa, A.K.
History
DepositionJan 26, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2026Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2026Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Plasma kallikrein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7682
Polymers34,3131
Non-polymers4551
Water4,522251
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.766, 59.503, 105.863
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Plasma kallikrein / Fletcher factor / Kininogenin / Plasma prekallikrein / PKK


Mass: 34312.844 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KLKB1, KLK3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P03952, plasma kallikrein
#2: Chemical ChemComp-A1C6O / (3'R)-1'-(1-benzyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one


Mass: 454.881 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20ClFN4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 251 / 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: 1.92 Å3/Da / Density % sol: 35.83 % / Description: ROD
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 0.1 M HEPES, pH 7.0, 10-12% PEG8000 / PH range: 6.9 - 7.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.779→51.871 Å / Num. obs: 26046 / % possible obs: 99.9 % / Observed criterion σ(F): 2.2 / Redundancy: 6.3 % / CC1/2: 0.998 / Net I/σ(I): 13.4
Reflection shellResolution: 1.779→1.809 Å / Num. unique obs: 1290 / CC1/2: 0.825

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Processing

Software
NameVersionClassification
autoBUSTER2.11.7refinement
autoPROC1.1.7data reduction
autoPROC1.1.7data scaling
MOLREP11.6.02phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.78→21.01 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.197 --
Rwork0.172 --
obs0.173 1245 99.9 %
Refinement stepCycle: LAST / Resolution: 1.78→21.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1894 0 32 251 2177

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