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- PDB-6t9t: Matriptase in complex with the synthetic inhibitor (S)-3-(3-(4-(3... -

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Entry
Database: PDB / ID: 6t9t
TitleMatriptase in complex with the synthetic inhibitor (S)-3-(3-(4-(3-(tert-butyl)ureido)piperidin-1-yl)-2-((3'-fluoro-4'-(hydroxymethyl)-[1,1'-biphenyl])-3-sulfonamido)-3-oxopropyl)benzimidamide (MI-1904)
ComponentsSuppressor of tumorigenicity 14 protein
KeywordsHYDROLASE / Matriptase / Complex / Ligand-binding
Function / homology
Function and homology information


matriptase / epithelial cell morphogenesis involved in placental branching / Formation of the cornified envelope / keratinocyte differentiation / serine-type peptidase activity / neural tube closure / protein catabolic process / basolateral plasma membrane / external side of plasma membrane / serine-type endopeptidase activity ...matriptase / epithelial cell morphogenesis involved in placental branching / Formation of the cornified envelope / keratinocyte differentiation / serine-type peptidase activity / neural tube closure / protein catabolic process / basolateral plasma membrane / external side of plasma membrane / serine-type endopeptidase activity / proteolysis / extracellular space / plasma membrane
Similarity search - Function
Peptidase S1A, matripase / SEA domain superfamily / SEA domain profile. / SEA domain / SEA domain / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily ...Peptidase S1A, matripase / SEA domain superfamily / SEA domain profile. / SEA domain / SEA domain / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / 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-MXH / Suppressor of tumorigenicity 14 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsMueller, J.M. / Merkl, S. / Keils, A. / Pilgram, O. / Steinmetzer, T.
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Improving the selectivity of 3-amidinophenylalanine-derived matriptase inhibitors
Authors: Pilgram, O. / Keils, A. / Benary, G.E. / Muller, J. / Merkl, S. / Ngaha, S. / Huber, S. / Chevillard, F. / Harbig, A. / Magdolen, V. / Heine, A. / Bottcher-Friebertshauser, E. / Steinmetzer, T.
History
DepositionOct 28, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 2.0Jul 7, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Refinement description / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / atom_type / entity / pdbx_distant_solvent_atoms / pdbx_nonpoly_scheme / pdbx_refine_tls / pdbx_refine_tls_group / pdbx_struct_special_symmetry / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_torsion / refine / refine_hist / refine_ls_restr / refine_ls_shell / reflns / software / struct_conn / struct_site / struct_site_gen
Item: _entity.pdbx_number_of_molecules / _pdbx_validate_torsion.phi ..._entity.pdbx_number_of_molecules / _pdbx_validate_torsion.phi / _pdbx_validate_torsion.psi / _refine.B_iso_mean / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_d_res_low / _refine.ls_number_reflns_R_work / _refine.ls_percent_reflns_R_free / _refine.ls_percent_reflns_obs / _refine.overall_SU_ML / _refine.pdbx_ls_sigma_F / _refine.pdbx_overall_phase_error / _refine.pdbx_stereochemistry_target_values / _refine.solvent_model_details / _refine_hist.d_res_low / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_protein / _refine_ls_restr.dev_ideal / _refine_ls_restr.number / _refine_ls_shell.R_factor_R_free / _refine_ls_shell.R_factor_R_work / _refine_ls_shell.d_res_high / _refine_ls_shell.d_res_low / _refine_ls_shell.number_reflns_R_work / _refine_ls_shell.percent_reflns_obs / _reflns.B_iso_Wilson_estimate / _reflns.d_resolution_high / _struct_conn.pdbx_dist_value
Description: Ligand geometry
Details: Data was re-evaluated and an alternative conformation of ligand was deemed reasonable. The structure was then refined further to reflect the best model fit.
Provider: author / Type: Coordinate replacement
Revision 2.1Jun 1, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.3Nov 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

Downloads & links

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Assembly

Deposited unit
A: Suppressor of tumorigenicity 14 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,1363
Polymers26,4481
Non-polymers6882
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-4 kcal/mol
Surface area10360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.687, 80.408, 40.714
Angle α, β, γ (deg.)90.000, 95.710, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-503-

HOH

21A-541-

HOH

31A-571-

HOH

41A-610-

HOH

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Components

#1: Protein Suppressor of tumorigenicity 14 protein / Matriptase / Membrane-type serine protease 1 / MT-SP1 / Prostamin / Serine protease 14 / Serine ...Matriptase / Membrane-type serine protease 1 / MT-SP1 / Prostamin / Serine protease 14 / Serine protease TADG-15 / Tumor-associated differentially-expressed gene 15 protein


Mass: 26447.689 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ST14, PRSS14, SNC19, TADG15 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y5Y6, matriptase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-MXH / 1-~{tert}-butyl-3-[1-[(2~{S})-3-(3-carbamimidoylphenyl)-2-[[3-[3-fluoranyl-4-(hydroxymethyl)phenyl]phenyl]sulfonylamino ]propanoyl]piperidin-4-yl]urea / (S)-3-(3-(4-(3-(tert-butyl)ureido)piperidin-1-yl)-2-((3'-fluoro-4'-(hydroxymethyl)-[1,1'-biphenyl])-3-sulfonamido)-3-ox opropyl)benzimidamide


Mass: 652.779 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H41FN6O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.37 Å3/Da / Density % sol: 48.05 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 100 mM Sodium acetate pH 4.6, 2 M Sodium formate, protein concentration 7 mg/ml

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.68644987696→50 Å / Num. obs: 27322 / % possible obs: 97.5 % / Redundancy: 3.78 % / Biso Wilson estimate: 18.9933085518 Å2 / CC1/2: 0.999 / Rsym value: 0.062 / Net I/σ(I): 13.48
Reflection shellResolution: 1.69→1.79 Å / Redundancy: 3.82 % / Mean I/σ(I) obs: 2.41 / Num. unique obs: 4365 / CC1/2: 0.815 / Rsym value: 0.485 / % possible all: 97.6

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PHENIX1.10.1_2155refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GV6

2gv6


Resolution: 1.69→40.5119860988 Å / SU ML: 0.178274532055 / Cross valid method: FREE R-VALUE / σ(F): 1.35315402303 / Phase error: 22.778754605
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.201903857021 1352 5.00351578402 %
Rwork0.170323632146 25669 -
obs0.171933711265 27021 97.4853885562 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.5897796376 Å2
Refinement stepCycle: LAST / Resolution: 1.69→40.5119860988 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1828 0 47 211 2086
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009364506448352009
X-RAY DIFFRACTIONf_angle_d1.013118681172748
X-RAY DIFFRACTIONf_chiral_restr0.0669269745891283
X-RAY DIFFRACTIONf_plane_restr0.00786004161302404
X-RAY DIFFRACTIONf_dihedral_angle_d13.77201566041198
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.74670.3224460114021340.2381466825752534X-RAY DIFFRACTION96.5267727931
1.7467-1.81670.2865808434031360.2070772285652591X-RAY DIFFRACTION99.3442622951
1.8167-1.89930.2322724428931370.199525104792598X-RAY DIFFRACTION99.0583122057
1.8993-1.99950.2891029094711290.2729713649882451X-RAY DIFFRACTION93.2754880694
1.9995-2.12470.2129191818651380.1682987809392622X-RAY DIFFRACTION99.2448759439
2.1247-2.28880.2982621489481280.2165546010162432X-RAY DIFFRACTION93.1586608443
2.2888-2.51910.2028092188261370.1611422337222604X-RAY DIFFRACTION98.6326016553
2.5191-2.88350.2080913612581370.1661900810992602X-RAY DIFFRACTION98.7027027027
2.8835-3.63260.1615748645181370.1480509760132608X-RAY DIFFRACTION98.8476773497
3.6326-40.51198609880.1500303584971390.1385417653752627X-RAY DIFFRACTION98.0155917789
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.466848364001-0.1875582864270.01157035788451.589698204810.5802271398510.339215320372-0.00346996544577-0.0533944184198-0.1307564143690.0814615800226-0.04356747416980.2092537824210.0749554761847-0.08060655438655.04539356004E-50.140088166065-0.01124636918920.01324624303510.1506120463070.01671499138970.1679865030512.558211976-22.583428290145.9926547162
20.834203301316-0.0317942879029-0.09066124466770.5879860910280.2839585116190.154709175845-0.0582405142634-0.122291442714-0.146794755738-0.001061820002270.0508850129564-0.02950667114720.108223220823-0.0174796806477-4.20205183738E-70.167355027380.002813629266840.0003374171075530.1520089380190.03117149691310.1407162959621.6547196701-22.71416660748.347091189
30.108255377706-0.0823650671926-0.07487380621510.10037525036-0.02756622943450.2227165518430.0835964818841-0.0292851416620.0647455120451-0.0635874095634-0.0282503343382-0.0903581518331-0.07344344147070.03827887194358.62504193415E-80.1655657802390.01029926337660.01108202841950.139130644968-0.002129102350390.17401441979223.3407114232-4.5257409936941.8148993866
40.458039192891-0.4662270418470.1816985851110.559995506366-0.05830930232930.226619946472-0.0397146218791-0.1823472707850.079615747212-0.00353923296706-0.04234400746710.196283505152-0.0727131852323-0.1442164139890.0006205146451840.1234750806530.00117600389198-0.007412386544140.164699624793-0.03168806202770.16246817357412.3275062877-4.6366324360549.846977247
50.855246977867-0.5061554409050.263001880160.737047664805-0.0779784241670.07019343708910.0238511105864-0.01610994503330.0820786949644-0.00482645577972-0.01690702682110.0518699312849-0.06931774660230.00848306850995-6.83076148693E-60.1482136146490.00874123334255-0.001234062860570.143026736110.002283619135870.12575003165419.1831741446-8.0041108492747.5749642174
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 16 through 80 )
2X-RAY DIFFRACTION2chain 'A' and (resid 81 through 123 )
3X-RAY DIFFRACTION3chain 'A' and (resid 124 through 140 )
4X-RAY DIFFRACTION4chain 'A' and (resid 141 through 179 )
5X-RAY DIFFRACTION5chain 'A' and (resid 180 through 244 )

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