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

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Basic information

Entry
Database: PDB / ID: 10mw
TitleN-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors compound 25 ((3'R)-1'-{(1P)-5-amino-1-[2-(trifluoromethoxy)phenyl]-1H-pyrazole-4-carbonyl}-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one)
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 / 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 / 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: 1.62 Å
AuthorsMerchant, R.R. / Chernyak, N. / Lopez, J.A. / Sharp, P.P. / Mandal, M. / Je, J. / Hruza, A. / Rearden, P. / Tatosian, D.A. / Lin, K. ...Merchant, R.R. / Chernyak, N. / Lopez, J.A. / Sharp, P.P. / Mandal, M. / Je, J. / Hruza, A. / Rearden, P. / Tatosian, D.A. / Lin, K. / Esmay, J. / Yang, S. / Cheng, A. / Ellsworth, K. / Poiou, T. / Fier, P. / Hicks, J. / Sinz, C. / Ogawa, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
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 28, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2026Provider: repository / Type: Initial release

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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)31,8384
Polymers30,8821
Non-polymers9563
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area580 Å2
ΔGint7 kcal/mol
Surface area11350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.527, 77.977, 47.568
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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


Mass: 30881.844 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP residues 376-638)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KLKB1, KLK3 / Production host: Komagataella pastoris (fungus) / References: UniProt: P03952, plasma kallikrein
#2: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#3: Chemical ChemComp-A1C6Z / (3'R)-1'-{(1P)-5-amino-1-[2-(trifluoromethoxy)phenyl]-1H-pyrazole-4-carbonyl}-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one


Mass: 539.867 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18ClF4N5O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 37.49 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1 M MES, pH 6.5, 24% PEG8000, 5% glycerol / PH range: 6.2 - 6.7

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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 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.62→50.163 Å / Num. obs: 21821 / % possible obs: 88.7 % / Redundancy: 6.4 % / CC1/2: 0.999 / Net I/σ(I): 15.4
Reflection shellResolution: 1.63→1.791 Å / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1051 / CC1/2: 0.638

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Processing

Software
NameVersionClassification
autoBUSTER2.11.7refinement
autoPROC1.1.7data reduction
STARANISO1.1.7data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→47.57 Å / SU R Cruickshank DPI: 0.223 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.158 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.132
RfactorNum. reflection% reflection
Rfree0.234 1058 4.85 %
Rwork0.209 --
obs0.21 21821 69.2 %
Displacement parametersBiso mean: 35.24 Å2
Baniso -1Baniso -2Baniso -3
1--0.5062 Å20 Å20 Å2
2---0.1644 Å20 Å2
3---0.6706 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.62→47.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1850 0 63 170 2083
LS refinement shellResolution: 1.62→1.73 Å
RfactorNum. reflection% reflection
Rfree0.234 23 5.26 %
Rwork0.2092 414 -
obs--8.1 %

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