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

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Basic information

Entry
Database: PDB / ID: 8bfw
TitleThe structures of Ace2 in complex with bicyclic peptide inhibitor
Components
  • ALA-CYS-VAL-ARG-SER-HIS-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 / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction ...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 / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction / peptidyl-dipeptidase activity / maternal process involved in female pregnancy / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / negative regulation of signaling receptor activity / carboxypeptidase activity / Attachment and Entry / positive regulation of cardiac muscle contraction / viral life cycle / regulation of cytokine production / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / brush border membrane / regulation of transmembrane transporter activity / cilium / negative regulation of ERK1 and ERK2 cascade / positive regulation of reactive oxygen species metabolic process / metallopeptidase activity / endocytic vesicle membrane / virus receptor activity / regulation of cell population proliferation / regulation of inflammatory response / endopeptidase activity / Potential therapeutics for SARS / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / receptor-mediated endocytosis of virus by host cell / membrane fusion / Attachment and Entry / 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 / identical protein binding / membrane / plasma membrane
Similarity search - Function
Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / 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: 2.33 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
DepositionOct 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 4, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 23, 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: Processed angiotensin-converting enzyme 2
B: ALA-CYS-VAL-ARG-SER-HIS-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
C: Processed angiotensin-converting enzyme 2
D: ALA-CYS-VAL-ARG-SER-HIS-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)145,8696
Polymers144,8854
Non-polymers9842
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2610 Å2
ΔGint-9 kcal/mol
Surface area25560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.937, 76.966, 124.226
Angle α, β, γ (deg.)90.00, 108.93, 90.00
Int Tables number4
Space group name H-MP1211

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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-HIS-CYS-SER-SER-LEU-LEU-PRO-ARG-ILE-HIS-CYS-ALA-NH2


Mass: 1855.241 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.53 Å3/Da / Density % sol: 51.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.6 / Details: 0.02 M CaCl2, 0.1 M Na Acet, 30 %v/v MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 24, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.33→58.75 Å / Num. obs: 61909 / % possible obs: 99.8 % / Redundancy: 11 % / CC1/2: 0.997 / Rmerge(I) obs: 0.281 / Rpim(I) all: 0.088 / Rrim(I) all: 0.295 / Net I/σ(I): 3.9 / Num. measured all: 679243
Reflection shellResolution: 2.33→2.37 Å / Redundancy: 10.6 % / Num. unique obs: 2911 / CC1/2: 0.2 / Rpim(I) all: 3.706 / Rrim(I) all: 12.152

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
xia23.3.3data scaling
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R42

1r42


Resolution: 2.33→58.75 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.901 / SU B: 36.172 / SU ML: 0.674 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.806 / ESU R Free: 0.385 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.323 2354 4.8 %RANDOM
Rwork0.249 ---
obs0.253 46649 79.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 66.03 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20 Å2-4.24 Å2
2---2.03 Å20 Å2
3---3.78 Å2
Refinement stepCycle: LAST / Resolution: 2.33→58.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9975 0 0 21 9996
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01310356
X-RAY DIFFRACTIONr_bond_other_d0.0030.0169375
X-RAY DIFFRACTIONr_angle_refined_deg1.4061.6414077
X-RAY DIFFRACTIONr_angle_other_deg1.171.57721623
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.19651232
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.5623.722575
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.698151723
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0551540
X-RAY DIFFRACTIONr_chiral_restr0.0570.21274
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211879
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022469
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.33→2.39 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.704 7 -
Rwork0.634 138 -
obs--3.18 %

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