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- PDB-1z8g: Crystal structure of the extracellular region of the transmembran... -

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Basic information

Entry
Database: PDB / ID: 1z8g
TitleCrystal structure of the extracellular region of the transmembrane serine protease hepsin with covalently bound preferred substrate.
Components
  • ACE-LYS-GLN-LEU-ARG-Chloromethylketone
  • Serine protease hepsin
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE HEPSIN / PROTEASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


hepsin / pilomotor reflex / Signaling by MST1 / positive regulation of thyroid hormone generation / cochlea morphogenesis / serine-type exopeptidase activity / basement membrane disassembly / positive regulation of plasminogen activation / detection of mechanical stimulus involved in sensory perception of sound / negative regulation of epithelial to mesenchymal transition ...hepsin / pilomotor reflex / Signaling by MST1 / positive regulation of thyroid hormone generation / cochlea morphogenesis / serine-type exopeptidase activity / basement membrane disassembly / positive regulation of plasminogen activation / detection of mechanical stimulus involved in sensory perception of sound / negative regulation of epithelial to mesenchymal transition / MET Receptor Activation / response to thyroid hormone / positive regulation of hepatocyte proliferation / positive regulation by host of viral transcription / potassium ion transmembrane transport / serine-type peptidase activity / negative regulation of epithelial cell proliferation / cell-cell junction / peptidase activity / regulation of cell shape / positive regulation of cell growth / apical plasma membrane / serine-type endopeptidase activity / neuronal cell body / endoplasmic reticulum membrane / positive regulation of gene expression / negative regulation of apoptotic process / cell surface / proteolysis / extracellular exosome / membrane / plasma membrane
Similarity search - Function
Hepsin, SRCR domain / Hepsin, SRCR domain / Mac-2 Binding Protein / SRCR-like domain / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family ...Hepsin, SRCR domain / Hepsin, SRCR domain / Mac-2 Binding Protein / SRCR-like domain / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / 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. / Trypsin-like serine protease / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Roll / Peptidase S1, PA clan / Beta Barrel / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
N-acetyl-6-ammonio-L-norleucyl-L-glutaminyl-N-[(1S)-4-{[amino(iminio)methyl]amino}-1-(chloroacetyl)butyl]-L-leucinamide / Serine protease hepsin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsHerter, S. / Piper, D.E. / Aaron, W. / Gabriele, T. / Cutler, G. / Cao, P. / Bhatt, A.S. / Choe, Y. / Craik, C.S. / Walker, N. ...Herter, S. / Piper, D.E. / Aaron, W. / Gabriele, T. / Cutler, G. / Cao, P. / Bhatt, A.S. / Choe, Y. / Craik, C.S. / Walker, N. / Meininger, D. / Hoey, T. / Austin, R.J.
CitationJournal: Biochem.J. / Year: 2005
Title: Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers
Authors: Herter, S. / Piper, D.E. / Aaron, W. / Gabriele, T. / Cutler, G. / Cao, P. / Bhatt, A.S. / Choe, Y. / Craik, C.S. / Walker, N. / Meininger, D. / Hoey, T. / Austin, R.J.
History
DepositionMar 30, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_conn / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details
Revision 1.5Aug 23, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Remark 999 SEQUENCE RESIDUES 160-162 ARE DISORDERED. THIS PEPTIDE BOND CLEAVAGE OCCURS DURING THE ACTIVATION ... SEQUENCE RESIDUES 160-162 ARE DISORDERED. THIS PEPTIDE BOND CLEAVAGE OCCURS DURING THE ACTIVATION OF THE PROTEASE.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine protease hepsin
L: ACE-LYS-GLN-LEU-ARG-Chloromethylketone


Theoretical massNumber of molelcules
Total (without water)41,0552
Polymers41,0552
Non-polymers00
Water8,305461
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1510 Å2
ΔGint-2 kcal/mol
Surface area15330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.705, 47.633, 67.791
Angle α, β, γ (deg.)90.00, 108.24, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Serine protease hepsin / Transmembrane protease / serine 1


Mass: 40448.766 Da / Num. of mol.: 1 / Mutation: N112A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPN, TMPRSS1 / Production host: Pichia pastoris (fungus)
References: UniProt: P05981, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Protein/peptide ACE-LYS-GLN-LEU-ARG-Chloromethylketone


Type: Peptide-like / Class: Inhibitor / Mass: 606.202 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: THE PEPTIDE WAS CHEMICALLY SYNTHESIZED.
References: N-acetyl-6-ammonio-L-norleucyl-L-glutaminyl-N-[(1S)-4-{[amino(iminio)methyl]amino}-1-(chloroacetyl)butyl]-L-leucinamide
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 461 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE UNBOUND FORM OF THE INHIBITOR (CHAIN L) IS ACE-LYS-GLN-LEU-ARG-CHLOROMETHYLKETONE. UPON ...THE UNBOUND FORM OF THE INHIBITOR (CHAIN L) IS ACE-LYS-GLN-LEU-ARG-CHLOROMETHYLKETONE. UPON REACTION WITH PROTEIN IT FORMS TWO COVALENT BONDS: 1) A COVALENT BOND TO OG SER 353 FORMING A HEMIKETAL AR7 AND 2) A COVALENT BOND TO NE2 OF HIS 203. THE CHLORINE OF CHLOROMETHYLKETONE MOIETY 0QE IS LEAVING AS A RESULT OF THE FORMATION OF THE COVALENT BOND BETWEEN THE INHIBITOR AND THE PROTEIN.
Sequence detailsTHERE IS A CHAIN BREAK BETWEEN RESIDUES 162 AND 163 (RESIDUES 160-162 ARE DISORDERED). THIS PEPTIDE ...THERE IS A CHAIN BREAK BETWEEN RESIDUES 162 AND 163 (RESIDUES 160-162 ARE DISORDERED). THIS PEPTIDE BOND CLEAVAGE OCCURS DURING THE ACTIVATION OF THE PROTEASE.

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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: 2.16 Å3/Da / Density % sol: 42.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: PEG 3350, ammonium fluoride, Na-cacodylate, pH 5.6, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 6, 2004 / Details: OSMIC CONFOCAL OPTIC (GREEN)
RadiationMonochromator: OSMIC MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.55→23.9 Å / Num. all: 46843 / Num. obs: 46843 / % possible obs: 95 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 6 % / Biso Wilson estimate: 17 Å2 / Rmerge(I) obs: 0.056 / Net I/σ(I): 21.6
Reflection shellResolution: 1.55→1.61 Å / Rmerge(I) obs: 0.327 / Mean I/σ(I) obs: 2.1 / % possible all: 59.2

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Processing

Software
NameVersionClassification
DENZOdata reduction
TRUNCATEdata reduction
CNSrefinement
CCP4(TRUNCATE)data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1EKB

1ekb


Resolution: 1.55→23.9 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.217 2367 RANDOM
Rwork0.196 --
all0.198 46821 -
obs0.198 46821 -
Refinement stepCycle: LAST / Resolution: 1.55→23.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2829 0 0 461 3290
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.004315
X-RAY DIFFRACTIONc_angle_deg1.28876

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