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- PDB-8wxw: Falcilysin in complex with hemoglobin alpha chain peptide -

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Basic information

Entry
Database: PDB / ID: 8wxw
TitleFalcilysin in complex with hemoglobin alpha chain peptide
Components
  • Falcilysin
  • Hemoglobin subunit alpha fragment
KeywordsHYDROLASE / falcilysin-substrate complex / inactive mutant
Function / homology
Function and homology information


hemoglobin catabolic process / apicoplast / food vacuole / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / vacuolar membrane / nitric oxide transport / cellular oxidant detoxification / haptoglobin-hemoglobin complex / hemoglobin complex / oxygen transport ...hemoglobin catabolic process / apicoplast / food vacuole / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / vacuolar membrane / nitric oxide transport / cellular oxidant detoxification / haptoglobin-hemoglobin complex / hemoglobin complex / oxygen transport / Scavenging of heme from plasma / endocytic vesicle lumen / oxygen carrier activity / hydrogen peroxide catabolic process / carbon dioxide transport / response to hydrogen peroxide / Heme signaling / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen / Cytoprotection by HMOX1 / oxygen binding / metalloendopeptidase activity / protein processing / blood microparticle / iron ion binding / inflammatory response / heme binding / extracellular space / extracellular exosome / extracellular region / metal ion binding / membrane / cytosol
Similarity search - Function
: / Peptidase M16C associated / Peptidase M16C associated / PreP C-terminal domain / Peptidase M16C associated / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like ...: / Peptidase M16C associated / Peptidase M16C associated / PreP C-terminal domain / Peptidase M16C associated / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like / Hemoglobin, pi / Hemoglobin, alpha-type / : / Globin/Protoglobin / Globin / Globin / Globin domain profile. / Globin-like superfamily
Similarity search - Domain/homology
Hemoglobin subunit alpha / Falcilysin
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsLin, J.Q. / Lescar, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Biol / Year: 2024
Title: Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition.
Authors: Jianqing Lin / Xinfu Yan / Zara Chung / Chong Wai Liew / Abbas El Sahili / Evgeniya V Pechnikova / Peter R Preiser / Zbynek Bozdech / Yong-Gui Gao / Julien Lescar /
Abstract: In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, ...In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains respectively. An antiparallel β-sheet is formed between the substrate and enzyme, accounting for sequence-independent recognition at positions P2 and P1. In contrast, numerous contacts favor tyrosine and phenylalanine at the P1' position of the substrate. Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation. Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state. These structures give atomic level pictures of the proteolytic cycle, in which falcilysin interconverts between a closed state conducive to proteolysis, and an open conformation amenable to substrate diffusion and products release. MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition. These data should inform the design of potent inhibitors of falcilysin to combat malaria.
History
DepositionOct 30, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _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: Falcilysin
P: Hemoglobin subunit alpha fragment
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,45014
Polymers136,7412
Non-polymers70912
Water13,727762
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3430 Å2
ΔGint-106 kcal/mol
Surface area42890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.120, 105.720, 125.360
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AP

#1: Protein Falcilysin


Mass: 135038.375 Da / Num. of mol.: 1 / Mutation: E132Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: FLN, PF3D7_1360800 / Production host: Escherichia coli (E. coli)
References: UniProt: Q76NL8, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
#2: Protein/peptide Hemoglobin subunit alpha fragment


Mass: 1702.901 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P69905

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Non-polymers , 5 types, 774 molecules

#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 762 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.28 Å3/Da / Density % sol: 46.07 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 4% w/v PEG 1500, 20% v/v glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.6→48 Å / Num. obs: 104687 / % possible obs: 99.9 % / Redundancy: 13.7 % / Biso Wilson estimate: 33 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.08883 / Rpim(I) all: 0.02493 / Net I/σ(I): 19.1
Reflection shellResolution: 1.864→1.931 Å / Redundancy: 13.7 % / Num. unique obs: 10280 / CC1/2: 0.771 / CC star: 0.933 / % possible all: 99.17

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Processing

Software
NameVersionClassification
PHENIX1.21.1-5286-0000refinement
XDSdata reduction
XDSdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.86→46.09 Å / SU ML: 0.2455 / Cross valid method: FREE R-VALUE / σ(F): 1.3 / Phase error: 22.9907
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2096 10059 4.99 %
Rwork0.1889 191342 -
obs0.19 104647 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.72 Å2
Refinement stepCycle: LAST / Resolution: 1.86→46.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8916 0 35 762 9713
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01019131
X-RAY DIFFRACTIONf_angle_d1.262412290
X-RAY DIFFRACTIONf_chiral_restr0.07171341
X-RAY DIFFRACTIONf_plane_restr0.00641566
X-RAY DIFFRACTIONf_dihedral_angle_d12.95473465
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.890.43833270.39976170X-RAY DIFFRACTION96.31
1.89-1.910.32253360.32656374X-RAY DIFFRACTION99.94
1.91-1.930.35723400.30496390X-RAY DIFFRACTION99.97
1.93-1.960.3183330.2796380X-RAY DIFFRACTION100
1.96-1.980.27853350.26836374X-RAY DIFFRACTION99.96
1.98-2.010.28453350.25196387X-RAY DIFFRACTION99.96
2.01-2.040.25313360.24366364X-RAY DIFFRACTION99.97
2.04-2.070.27263390.22846390X-RAY DIFFRACTION99.97
2.07-2.10.23383330.2236390X-RAY DIFFRACTION100
2.1-2.130.24783370.22256407X-RAY DIFFRACTION100
2.13-2.170.2313340.21936369X-RAY DIFFRACTION100
2.17-2.210.23773360.2156405X-RAY DIFFRACTION99.97
2.21-2.250.25563320.21966424X-RAY DIFFRACTION100
2.25-2.30.24093330.21466351X-RAY DIFFRACTION100
2.3-2.350.23323360.20586391X-RAY DIFFRACTION99.97
2.35-2.40.20473280.20326397X-RAY DIFFRACTION100
2.4-2.460.23043400.20576349X-RAY DIFFRACTION100
2.46-2.530.23353420.26439X-RAY DIFFRACTION100
2.53-2.60.21833410.19966342X-RAY DIFFRACTION100
2.6-2.690.25623370.19776392X-RAY DIFFRACTION100
2.69-2.780.22633340.19536403X-RAY DIFFRACTION100
2.78-2.90.22223320.19536362X-RAY DIFFRACTION100
2.9-3.030.20833430.19966387X-RAY DIFFRACTION100
3.03-3.190.21283280.18536377X-RAY DIFFRACTION100
3.19-3.390.19233360.1786396X-RAY DIFFRACTION99.97
3.39-3.650.19833360.16176398X-RAY DIFFRACTION100
3.65-4.020.16743320.15726386X-RAY DIFFRACTION100
4.02-4.60.16363390.14556391X-RAY DIFFRACTION99.99
4.6-5.790.183330.16936374X-RAY DIFFRACTION100
5.79-46.090.18683360.17456383X-RAY DIFFRACTION99.93

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