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- EMDB-37940: Partially closed falcilysin, from free falcilysin dataset -

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Basic information

Entry
Database: EMDB / ID: EMD-37940
TitlePartially closed falcilysin, from free falcilysin dataset
Map data
Sample
  • Complex: Falcilysin
    • Protein or peptide: Falcilysin
  • Ligand: ZINC ION
Keywordsfalcilysin partially closed conformation / HYDROLASE
Function / homology
Function and homology information


hemoglobin catabolic process / apicoplast / food vacuole / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / vacuolar membrane / metalloendopeptidase activity / protein processing / metal ion binding
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
Similarity search - Domain/homology
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLin JQ / Yan XF / Lescar J
Funding support Singapore, 1 items
OrganizationGrant numberCountry
Not funded Singapore
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 31, 2023-
Header (metadata) releaseAug 7, 2024-
Map releaseAug 7, 2024-
UpdateFeb 19, 2025-
Current statusFeb 19, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37940.png

Downloads & links

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Map

FileDownload / File: emd_37940.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 128 pix.
= 146.688 Å		1.15 Å/pix.
x 128 pix.
= 146.688 Å		1.15 Å/pix.
x 128 pix.
= 146.688 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.146 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.043598875 - 0.07696556
Average (Standard dev.)0.00048178542 (±0.004567958)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 146.688 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_37940_msk_1.map
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Additional map: #2

Fileemd_37940_additional_1.map
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Additional map: #1

Fileemd_37940_additional_2.map
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Half map: #2

Fileemd_37940_half_map_1.map
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Half map: #1

Fileemd_37940_half_map_2.map
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Sample components

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Entire : Falcilysin

EntireName: Falcilysin
Components
  • Complex: Falcilysin
    • Protein or peptide: Falcilysin
  • Ligand: ZINC ION

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Supramolecule #1: Falcilysin

SupramoleculeName: Falcilysin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: Falcilysin

MacromoleculeName: Falcilysin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 132.220375 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EWIHEKSPKH NSYDIIEKRY NEEFKMTYTV YQHKKAKTQV ISLGTNDPLD VEQAFAFYVK TLTHSGKGIP HILEHSVLSG SKNYNYKNS IGLLEKGTLH THLNAYTFND RTVYMAGSMN NKDFFNIMGV YMDSVFQPNV LENKYIFETE GWTYEVEKLK E DEKGKAEI ...String:
EWIHEKSPKH NSYDIIEKRY NEEFKMTYTV YQHKKAKTQV ISLGTNDPLD VEQAFAFYVK TLTHSGKGIP HILEHSVLSG SKNYNYKNS IGLLEKGTLH THLNAYTFND RTVYMAGSMN NKDFFNIMGV YMDSVFQPNV LENKYIFETE GWTYEVEKLK E DEKGKAEI PQMKDYKVSF NGIVYNEMKG ALSSPLEDLY HEEMKYMFPD NVHSNNSGGD PKEITNLTYE EFKEFYYKNY NP KKVKVFF FSKNNPTELL NFVDQYLGQL DYSKYRDDAV ESVEYQTYKK GPFYIKKKYG DHSEEKENLV SVAWLLNPKV DKT NNHNNN HSNNQSSENN GYSNGSHSSD LSLENPTDYF VLLIINNLLI HTPESVLYKA LTDCGLGNNV IDRGLNDSLV QYIF SIGLK GIKRNNEKIK NFDKVHYEVE DVIMNALKKV VKEGFNKSAV EASINNIEFI LKEANLKTSK SIDFVFEMTS KLNYN RDPL LIFEFEKYLN IVKNKIKNEP MYLEKFVEKH FINNAHRSVI LLEGDENYAQ EQENLEKQEL KKRIENFNEQ EKEQVI KNF EELSKYKNAE ESPEHLNKFP IISISDLNKK TLEVPVNVYF TNINENNNIM ETYNKLKTNE HMLKDNMDVF LKKYVLK ND KHNTNNNNNN NNNMDYSFTE TKYEGNVPIL VYEMPTTGIV YLQFVFSLDH LTVDELAYLN LFKTLILENK TNKRSSED F VILREKNIGS MSANVALYSK DDHLNVTDKY NAQALFNLEM HVLSHKCNDA LNIALEAVKE SDFSNKKKVI DILKRKING MKTTFSEKGY AILMKYVKAH LNSKHYAHNI IYGYENYLKL QEQLELAEND FKTLENILVR IRNKIFNKKN LMVSVTSDYG ALKHLFVNS NESLKNLVSY FEENDKYIND MQNKVNDPTV MGWNEEIKSK KLFDEEKVKK EFFVLPTFVN SVSMSGILFK P GEYLDPSF TVIVAALKNS YLWDTVRGLN GAYGVFADIE YDGSVVFLSA RDPNLEKTLA TFRESAKGLR KMADTMTEND LL RYIINTI GTIDKPRRGI ELSKLSFLRL ISNESEQDRV EFRKRIMNTK KEDFYKFADL LESKVNEFEK NIVIITTKEK ANE YIANVD GEFKKVLI

UniProtKB: Falcilysin

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.5 mg/mL
BufferpH: 7.5 / Details: 20 mM Na HEPES, 300 mM NaCl, 0.5 mM TCEP, pH 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 50355
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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