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- PDB-8bn1: The structures of Ace2 in complex with bicyclic peptide inhibitor -

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Basic information

Entry
Database: PDB / ID: 8bn1
TitleThe structures of Ace2 in complex with bicyclic peptide inhibitor
Components
  • ALA-CYS-VAL-ARG-SER-4PH-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
  • Processed angiotensin-converting enzyme 2
KeywordsMEMBRANE PROTEIN / Cov-2-sars bind proteins
Function / homology
Function and homology information


positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / angiotensin-mediated drinking behavior / regulation of systemic arterial blood pressure by renin-angiotensin / tryptophan transport / positive regulation of gap junction assembly / regulation of vasoconstriction / regulation of cardiac conduction ...positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / angiotensin-mediated drinking behavior / regulation of systemic arterial blood pressure by renin-angiotensin / tryptophan transport / positive regulation of gap junction assembly / regulation of vasoconstriction / regulation of cardiac conduction / peptidyl-dipeptidase activity / angiotensin maturation / maternal process involved in female pregnancy / metallocarboxypeptidase activity / Metabolism of Angiotensinogen to Angiotensins / Attachment and Entry / carboxypeptidase activity / negative regulation of signaling receptor activity / positive regulation of cardiac muscle contraction / regulation of cytokine production / viral life cycle / blood vessel diameter maintenance / brush border membrane / regulation of transmembrane transporter activity / negative regulation of smooth muscle cell proliferation / cilium / negative regulation of ERK1 and ERK2 cascade / endocytic vesicle membrane / metallopeptidase activity / positive regulation of reactive oxygen species metabolic process / virus receptor activity / regulation of cell population proliferation / regulation of inflammatory response / endopeptidase activity / Induction of Cell-Cell Fusion / Potential therapeutics for SARS / entry receptor-mediated virion attachment to host cell / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / membrane fusion / receptor-mediated virion attachment to host cell / symbiont entry into host cell / membrane raft / apical plasma membrane / endoplasmic reticulum lumen / cell surface / extracellular space / extracellular exosome / zinc ion binding / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
Collectrin-like domain profile. / Collectrin domain / Renal amino acid transporter / Peptidase family M2 domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Chem-LFI / Angiotensin-converting enzyme 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsBrear, P. / Lulla, A. / Harman, M. / Dods, R. / Chen, L. / Bezerra, G. / Demydchuk, Y. / Stanway, S. / Hyvonen, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2023
Title: Structure-Guided Chemical Optimization of Bicyclic Peptide ( Bicycle ) Inhibitors of Angiotensin-Converting Enzyme 2.
Authors: Harman, M.A.J. / Stanway, S.J. / Scott, H. / Demydchuk, Y. / Bezerra, G.A. / Pellegrino, S. / Chen, L. / Brear, P. / Lulla, A. / Hyvonen, M. / Beswick, P.J. / Skynner, M.J.
History
DepositionNov 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Processed angiotensin-converting enzyme 2
B: Processed angiotensin-converting enzyme 2
C: ALA-CYS-VAL-ARG-SER-4PH-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
D: ALA-CYS-VAL-ARG-SER-4PH-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,1119
Polymers144,9314
Non-polymers1,1805
Water1,38777
1
A: Processed angiotensin-converting enzyme 2
D: ALA-CYS-VAL-ARG-SER-4PH-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,0885
Polymers72,4652
Non-polymers6233
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Processed angiotensin-converting enzyme 2
C: ALA-CYS-VAL-ARG-SER-4PH-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,0234
Polymers72,4652
Non-polymers5572
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)193.253, 55.793, 122.843
Angle α, β, γ (deg.)90.00, 114.09, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Processed angiotensin-converting enzyme 2


Mass: 70587.188 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2, UNQ868/PRO1885 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BYF1
#2: Protein/peptide ALA-CYS-VAL-ARG-SER-4PH-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2


Mass: 1878.295 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-LFI / 1-[3,5-bis(3-bromanylpropanoyl)-1,3,5-triazinan-1-yl]-3-bromanyl-propan-1-one / Chemical crosslinker


Mass: 492.002 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H18Br3N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 77 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.09 Å3/Da / Density % sol: 41.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 25 %v/v PEGSH (Precipitant) 10 %v/v Glycerol (Precipitant) 0.2 M MgCl2 (Salt) 0.1 M TRIS 8 pH (Buffer)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9179 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9179 Å / Relative weight: 1
ReflectionResolution: 2.61→112.23 Å / Num. obs: 36877 / % possible obs: 100 % / Redundancy: 15.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.349 / Rpim(I) all: 0.092 / Rrim(I) all: 0.361 / Net I/σ(I): 5.5 / Num. measured all: 679243
Reflection shell

% possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allDiffraction-ID
2.61-2.6615.86.3290.318500.3291.656.5441
7.08-112.2314.30.09630.419480.9970.0260.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
xia2data scaling
DIALSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R42

1r42


Resolution: 2.61→58.75 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.882 / SU B: 34.689 / SU ML: 0.637 / Cross valid method: THROUGHOUT / ESU R Free: 0.463 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.32464 1827 5 %RANDOM
Rwork0.25548 ---
obs0.25903 34960 99.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 72.392 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å20 Å2-0.82 Å2
2--8.44 Å2-0 Å2
3----5.18 Å2
Refinement stepCycle: 1 / Resolution: 2.61→58.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10013 0 3 77 10093
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01210309
X-RAY DIFFRACTIONr_bond_other_d0.0010.0169008
X-RAY DIFFRACTIONr_angle_refined_deg1.3091.64714000
X-RAY DIFFRACTIONr_angle_other_deg0.4771.56121052
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.37851222
X-RAY DIFFRACTIONr_dihedral_angle_2_deg12.6835.65246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.041101718
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0760.21460
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211660
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022096
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it5.2317.5034900
X-RAY DIFFRACTIONr_mcbond_other5.237.5044900
X-RAY DIFFRACTIONr_mcangle_it8.14211.2446118
X-RAY DIFFRACTIONr_mcangle_other8.14211.2456119
X-RAY DIFFRACTIONr_scbond_it4.2977.5235409
X-RAY DIFFRACTIONr_scbond_other4.2977.5235410
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.84111.2217883
X-RAY DIFFRACTIONr_long_range_B_refined11.94324190
X-RAY DIFFRACTIONr_long_range_B_other11.94324190
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.61→2.674 Å
RfactorNum. reflection% reflection
Rfree0.451 144 -
Rwork0.443 2392 -
obs--93.48 %

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