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- PDB-7k1v: Partial open state of Mycobacterium tuberculosis zinc metalloprot... -

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Basic information

Entry
Database: PDB / ID: 7k1v
TitlePartial open state of Mycobacterium tuberculosis zinc metalloprotease 1
ComponentsZinc metalloprotease
KeywordsHYDROLASE / Open state
Function / homology
Function and homology information


Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / protein processing / metalloendopeptidase activity / metal ion binding / plasma membrane
Similarity search - Function
Neprilysin-like (M13) protease domain profile. / Peptidase M13 / Peptidase M13, N-terminal domain / Peptidase M13, C-terminal domain / Peptidase M13, domain 2 / Peptidase family M13 / Peptidase family M13 / Metallopeptidase, catalytic domain superfamily
Similarity search - Domain/homology
Zinc metalloprotease / Probable zinc metalloprotease Zmp1
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsMancl, J.M. / Liang, W.G. / Zhao, M. / Tang, W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)R01 GM121964 United States
CitationJournal: Structure / Year: 2021
Title: Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states.
Authors: Wenguang G Liang / Jordan M Mancl / Minglei Zhao / Wei-Jen Tang /
Abstract: Zinc metalloprotease 1 (Zmp1), a Mycobacterium tuberculosis 75 kDa secreted enzyme, mediates key stages of tuberculosis disease progression. The biological activity of Zmp1 presumably stems from its ...Zinc metalloprotease 1 (Zmp1), a Mycobacterium tuberculosis 75 kDa secreted enzyme, mediates key stages of tuberculosis disease progression. The biological activity of Zmp1 presumably stems from its ability to degrade bacterium- and/or host-derived peptides. The crystal structures of Zmp1 and related M13 metalloproteases, such as neprilysin and endothelin-converting enzyme-1 were determined only in the closed conformation, which cannot capture substrates or release proteolytic products. Thus, the mechanisms of substrate binding and selectivity remain elusive. Here we report two open-state cryo-EM structures of Zmp1, revealed by our SAXS analysis to be the dominant states in solution. Our structural analyses reveal how ligand binding induces a conformational switch in four linker regions to drive the rigid body motion of the D1 and D2 domains, which form the sizable catalytic chamber. Furthermore, they offer insights into the catalytic cycle and mechanism of substrate recognition of M13 metalloproteases for future therapeutic innovations.
History
DepositionSep 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jul 14, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.title / _citation.year
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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Assembly

Deposited unit
A: Zinc metalloprotease


Theoretical massNumber of molelcules
Total (without water)78,0201
Polymers78,0201
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area31840 Å2

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Components

#1: Protein Zinc metalloprotease / Zinc metalloprotease 1


Mass: 78019.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)
Gene: pepO, zmp1, DSI38_14250, E5M52_00710, ERS007679_00756, ERS007681_00890, ERS007688_01723, ERS007720_00395, ERS007722_01585, ERS007741_01200, ERS013471_01326, ERS023446_01760, ERS075361_00622, ...Gene: pepO, zmp1, DSI38_14250, E5M52_00710, ERS007679_00756, ERS007681_00890, ERS007688_01723, ERS007720_00395, ERS007722_01585, ERS007741_01200, ERS013471_01326, ERS023446_01760, ERS075361_00622, ERS094182_00084, F6W99_02844, FRD82_01875
Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A0A045IRG4, UniProt: I6X8R2*PLUS, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Mycobacterium tuberculosis zinc metalloprotease partial open state
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)
Strain: ATCC 25618 / H37Rv
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria) / Strain: BL21(DE3)
Buffer solutionpH: 6.8
Details: 20 mM HEPES, pH 6.8, 150 mM NaCl, 0.5 mM BME, 20 mM Trimethylamine N-oxide dihydrate
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 308 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Image recordingAverage exposure time: 5 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
4CTFFIND4.1CTF correction
7PHENIXmodel fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
13PHENIXmodel refinement
14Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 8342000
3D reconstructionResolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 441846 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6XLY

6xly


Accession code: 6XLY / Source name: PDB / Type: experimental model

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