[English] 日本語
Yorodumi
- EMDB-37938: Partially closed Falcilysin bound to MK-4815, from MK-4815-treate... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-37938
TitlePartially closed Falcilysin bound to MK-4815, from MK-4815-treated dataset
Map datamap after 'auto-refine' in RELION, after 'Bayesian polishing'
Sample
  • Complex: Falcilysin
    • Protein or peptide: Falcilysin
  • Ligand: 2-(aminomethyl)-3,5-ditert-butyl-phenol
  • Ligand: ZINC ION
Keywordsfalcilysin partially closed conformation / MK-4815 binding / HYDROLASE
Function / homology
Function and homology information


hemoglobin catabolic process / apicoplast / food vacuole / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / vacuolar membrane / protein processing / metalloendopeptidase activity / 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: 2.7 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

-
Structure visualization

Supplemental images

emd_37938.png

Downloads & links

-
Map

FileDownload / File: emd_37938.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmap after 'auto-refine' in RELION, after 'Bayesian polishing'
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 128 pix.
= 148.48 Å		1.16 Å/pix.
x 128 pix.
= 148.48 Å		1.16 Å/pix.
x 128 pix.
= 148.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.16 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016
Minimum - Maximum-0.03654081 - 0.08960914
Average (Standard dev.)0.00009574618 (±0.0045482237)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 148.48 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Mask #1

Fileemd_37938_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Additional map: unmasked map from 'Post-processing' in RELION

Fileemd_37938_additional_1.map
Annotationunmasked map from 'Post-processing' in RELION
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Additional map: masked map from 'Post-processing' in RELION

Fileemd_37938_additional_2.map
Annotationmasked map from 'Post-processing' in RELION
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: half map 2

Fileemd_37938_half_map_1.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: half map 1

Fileemd_37938_half_map_2.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : Falcilysin

EntireName: Falcilysin
Components
  • Complex: Falcilysin
    • Protein or peptide: Falcilysin
  • Ligand: 2-(aminomethyl)-3,5-ditert-butyl-phenol
  • Ligand: ZINC ION

-
Supramolecule #1: Falcilysin

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

-
Macromolecule #1: Falcilysin

MacromoleculeName: Falcilysin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 135.039359 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MHHHHHHSSG VDLGTENLYF QSMEWIHEKS PKHNSYDIIE KRYNEEFKMT YTVYQHKKAK TQVISLGTND PLDVEQAFAF YVKTLTHSG KGIPHILEHS VLSGSKNYNY KNSIGLLEKG TLHTHLNAYT FNDRTVYMAG SMNNKDFFNI MGVYMDSVFQ P NVLENKYI ...String:
MHHHHHHSSG VDLGTENLYF QSMEWIHEKS PKHNSYDIIE KRYNEEFKMT YTVYQHKKAK TQVISLGTND PLDVEQAFAF YVKTLTHSG KGIPHILEHS VLSGSKNYNY KNSIGLLEKG TLHTHLNAYT FNDRTVYMAG SMNNKDFFNI MGVYMDSVFQ P NVLENKYI FETEGWTYEV EKLKEDEKGK AEIPQMKDYK VSFNGIVYNE MKGALSSPLE DLYHEEMKYM FPDNVHSNNS GG DPKEITN LTYEEFKEFY YKNYNPKKVK VFFFSKNNPT ELLNFVDQYL GQLDYSKYRD DAVESVEYQT YKKGPFYIKK KYG DHSEEK ENLVSVAWLL NPKVDKTNNH NNNHSNNQSS ENNGYSNGSH SSDLSLENPT DYFVLLIINN LLIHTPESVL YKAL TDCGL GNNVIDRGLN DSLVQYIFSI GLKGIKRNNE KIKNFDKVHY EVEDVIMNAL KKVVKEGFNK SAVEASINNI EFILK EANL KTSKSIDFVF EMTSKLNYNR DPLLIFEFEK YLNIVKNKIK NEPMYLEKFV EKHFINNAHR SVILLEGDEN YAQEQE NLE KQELKKRIEN FNEQEKEQVI KNFEELSKYK NAEESPEHLN KFPIISISDL NKKTLEVPVN VYFTNINENN NIMETYN KL KTNEHMLKDN MDVFLKKYVL KNDKHNTNNN NNNNNNMDYS FTETKYEGNV PILVYEMPTT GIVYLQFVFS LDHLTVDE L AYLNLFKTLI LENKTNKRSS EDFVILREKN IGSMSANVAL YSKDDHLNVT DKYNAQALFN LEMHVLSHKC NDALNIALE AVKESDFSNK KKVIDILKRK INGMKTTFSE KGYAILMKYV KAHLNSKHYA HNIIYGYENY LKLQEQLELA ENDFKTLENI LVRIRNKIF NKKNLMVSVT SDYGALKHLF VNSNESLKNL VSYFEENDKY INDMQNKVND PTVMGWNEEI KSKKLFDEEK V KKEFFVLP TFVNSVSMSG ILFKPGEYLD PSFTVIVAAL KNSYLWDTVR GLNGAYGVFA DIEYDGSVVF LSARDPNLEK TL ATFRESA KGLRKMADTM TENDLLRYII NTIGTIDKPR RGIELSKLSF LRLISNESEQ DRVEFRKRIM NTKKEDFYKF ADL LESKVN EFEKNIVIIT TKEKANEYIA NVDGEFKKVL IE

UniProtKB: Falcilysin

-
Macromolecule #2: 2-(aminomethyl)-3,5-ditert-butyl-phenol

MacromoleculeName: 2-(aminomethyl)-3,5-ditert-butyl-phenol / type: ligand / ID: 2 / Number of copies: 1 / Formula: H8F
Molecular weightTheoretical: 235.365 Da
Chemical component information

ChemComp-H8F:
2-(aminomethyl)-3,5-ditert-butyl-phenol

-
Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
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 %

-
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

+
Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 98298
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more