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- PDB-4a6l: beta-tryptase inhibitor -

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Basic information

Entry
Database: PDB / ID: 4a6l
Titlebeta-tryptase inhibitor
ComponentsTRYPTASE ALPHA/BETA-1
KeywordsHYDROLASE / INHIBITOR
Function / homology
Function and homology information


tryptase / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / serine-type peptidase activity / defense response / collagen-containing extracellular matrix / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular region / identical protein binding
Similarity search - Function
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 / Trypsin-like serine proteases ...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 / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-P43 / Tryptase beta-2 / Tryptase alpha/beta-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsMathieu, M. / Maignan, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Structure-Based Library Design and the Discovery of a Potent and Selective Mast Cell Beta-Tryptase Inhibitor as an Oral Therapeutic Agent.
Authors: Liang, G. / Aldous, S. / Merriman, G. / Levell, J. / Pribish, J. / Cairns, J. / Chen, X. / Maignan, S. / Mathieu, M. / Tsay, J. / Sides, K. / Rebello, S. / Whitely, B. / Morize, I. / Pauls, H.W.
History
DepositionNov 4, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 25, 2012Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "DB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "DB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TRYPTASE ALPHA/BETA-1
B: TRYPTASE ALPHA/BETA-1
C: TRYPTASE ALPHA/BETA-1
D: TRYPTASE ALPHA/BETA-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,5768
Polymers109,9664
Non-polymers1,6104
Water6,593366
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6250 Å2
ΔGint-41.5 kcal/mol
Surface area37940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.234, 82.234, 170.654
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.9998, 0.001393, -0.01965), (0.00288, -0.9764, -0.2157), (-0.01949, -0.2157, 0.9763)24.9, 95.61, 10.62
2given(-0.9616, -0.2745, 0.004226), (-0.2745, -0.9616, -0.006889), (0.005954, 0.005464, -1)13.9, 98.3, 0.129
3given(-0.965, 0.262, 0.006722), (0.2575, 0.9431, 0.2102), (0.04875, 0.2046, 0.9776)11.82, -0.7071, -10.03

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Components

#1: Protein
TRYPTASE ALPHA/BETA-1 / TRYPTASE-1 / TRYPTASE I / TRYPTASE ALPHA-1 / BETA-TRYPTASE


Mass: 27491.426 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: PICHIA PASTORIS (fungus) / References: UniProt: Q15661, UniProt: P20231*PLUS, tryptase
#2: Chemical
ChemComp-P43 / 1-{3-[1-({5-[(2-fluorophenyl)ethynyl]furan-2-yl}carbonyl)piperidin-4-yl]phenyl}methanamine


Mass: 402.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H23FN2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 366 / Source method: isolated from a natural source / Formula: H2O

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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: 2.53 Å3/Da / Density % sol: 51.1 % / Description: NONE
Crystal growpH: 5
Details: PEG 3000 10%, NAACETATE 100 MM PH 5, GLYCEROL 5%, NACL 1.7 M

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Dec 6, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.04→58.72 Å / Num. obs: 62107 / % possible obs: 86.8 % / Observed criterion σ(I): 0 / Redundancy: 1.9 % / Biso Wilson estimate: 34.76 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 19.1
Reflection shellResolution: 2.04→2.15 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 2.2 / % possible all: 81.8

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE STRUCTURE

Resolution: 2.05→30.01 Å / Cor.coef. Fo:Fc: 0.9356 / Cor.coef. Fo:Fc free: 0.9224 / SU R Cruickshank DPI: 0.211 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.206 / SU Rfree Blow DPI: 0.16 / SU Rfree Cruickshank DPI: 0.163
Details: THE P43 RESIDUES ARE THE INHIBITOR IN THE ACTIVE SITE.
RfactorNum. reflection% reflectionSelection details
Rfree0.2113 3140 5.07 %RANDOM
Rwork0.1884 ---
obs0.1896 61993 87.63 %-
Displacement parametersBiso mean: 32.72 Å2
Baniso -1Baniso -2Baniso -3
1-3.3731 Å20 Å20 Å2
2--3.3731 Å20 Å2
3----6.7463 Å2
Refine analyzeLuzzati coordinate error obs: 0.241 Å
Refinement stepCycle: LAST / Resolution: 2.05→30.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7648 0 120 366 8134
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018056HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0911056HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2532SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes204HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1180HARMONIC5
X-RAY DIFFRACTIONt_it8056HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.52
X-RAY DIFFRACTIONt_other_torsion17.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion972SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9157SEMIHARMONIC4
LS refinement shellResolution: 2.05→2.1 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.212 262 5.63 %
Rwork0.1943 4391 -
all0.1953 4653 -
obs--87.63 %

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