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- EMDB-34115: Structure of a mutated membrane-bound glycosyltransferase -

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Basic information

Entry
Database: EMDB / ID: EMD-34115
TitleStructure of a mutated membrane-bound glycosyltransferase
Map data
Sample
  • Complex: membrane-bound glycosyltransferase
    • Protein or peptide: 1,3-beta-glucan synthase component FKS1
  • Ligand: nonane
  • Ligand: DECANE
  • Ligand: TETRADECANE
  • Ligand: HEPTANE
  • Ligand: DODECANE
  • Ligand: (11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate
Keywordsmembrane protein / glycosyltransferase / TRANSFERASE
Function / homology
Function and homology information


fungal-type cell wall polysaccharide biosynthetic process / 1,3-beta-glucan synthase / 1,3-beta-D-glucan synthase activity / (1->3)-beta-D-glucan biosynthetic process / 1,3-beta-D-glucan synthase complex / fungal-type cell wall biogenesis / cellular bud / ascospore wall assembly / cellular bud tip / actin cortical patch ...fungal-type cell wall polysaccharide biosynthetic process / 1,3-beta-glucan synthase / 1,3-beta-D-glucan synthase activity / (1->3)-beta-D-glucan biosynthetic process / 1,3-beta-D-glucan synthase complex / fungal-type cell wall biogenesis / cellular bud / ascospore wall assembly / cellular bud tip / actin cortical patch / fungal-type cell wall / cellular bud neck / regulation of cell size / positive regulation of endocytosis / cell periphery / mitochondrion / plasma membrane
Similarity search - Function
Glycosyl transferase, family 48 / 1,3-beta-glucan synthase subunit FKS1-like, domain-1 / 1,3-beta-glucan synthase component / 1,3-beta-glucan synthase subunit FKS1, domain-1 / 1,3-beta-glucan synthase subunit FKS1
Similarity search - Domain/homology
1,3-beta-glucan synthase component FKS1
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsHu XL / Yang P / Zhang M / Liu XT / Yu HJ
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nature / Year: 2023
Title: Structural and mechanistic insights into fungal β-1,3-glucan synthase FKS1.
Authors: Xinlin Hu / Ping Yang / Changdong Chai / Jia Liu / Huanhuan Sun / Yanan Wu / Mingjie Zhang / Min Zhang / Xiaotian Liu / Hongjun Yu /
Abstract: The membrane-integrated synthase FKS is involved in the biosynthesis of β-1,3-glucan, the core component of the fungal cell wall. FKS is the target of widely prescribed antifungal drugs, including ...The membrane-integrated synthase FKS is involved in the biosynthesis of β-1,3-glucan, the core component of the fungal cell wall. FKS is the target of widely prescribed antifungal drugs, including echinocandin and ibrexafungerp. Unfortunately, the mechanism of action of FKS remains enigmatic and this has hampered development of more effective medicines targeting the enzyme. Here we present the cryo-electron microscopy structures of Saccharomyces cerevisiae FKS1 and the echinocandin-resistant mutant FKS1(S643P). These structures reveal the active site of the enzyme at the membrane-cytoplasm interface and a glucan translocation path spanning the membrane bilayer. Multiple bound lipids and notable membrane distortions are observed in the FKS1 structures, suggesting active FKS1-membrane interactions. Echinocandin-resistant mutations are clustered at a region near TM5-6 and TM8 of FKS1. The structure of FKS1(S643P) reveals altered lipid arrangements in this region, suggesting a drug-resistant mechanism of the mutant enzyme. The structures, the catalytic mechanism and the molecular insights into drug-resistant mutations of FKS1 revealed in this study advance the mechanistic understanding of fungal β-1,3-glucan biosynthesis and establish a foundation for developing new antifungal drugs by targeting FKS.
History
DepositionAug 18, 2022-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34115.png

Downloads & links

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Map

FileDownload / File: emd_34115.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 240 pix.
= 220.8 Å		0.92 Å/pix.
x 240 pix.
= 220.8 Å		0.92 Å/pix.
x 240 pix.
= 220.8 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.06836887 - 0.113015935
Average (Standard dev.)0.000038833536 (±0.003890688)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 220.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_34115_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_34115_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : membrane-bound glycosyltransferase

EntireName: membrane-bound glycosyltransferase
Components
  • Complex: membrane-bound glycosyltransferase
    • Protein or peptide: 1,3-beta-glucan synthase component FKS1
  • Ligand: nonane
  • Ligand: DECANE
  • Ligand: TETRADECANE
  • Ligand: HEPTANE
  • Ligand: DODECANE
  • Ligand: (11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate

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Supramolecule #1: membrane-bound glycosyltransferase

SupramoleculeName: membrane-bound glycosyltransferase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Molecular weightTheoretical: 215 KDa

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Macromolecule #1: 1,3-beta-glucan synthase component FKS1

MacromoleculeName: 1,3-beta-glucan synthase component FKS1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: 1,3-beta-glucan synthase
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: ATCC 204508 / S288c
Molecular weightTheoretical: 215.086203 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString: MNTDQQPYQG QTDYTQGPGN GQSQEQDYDQ YGQPLYPSQA DGYYDPNVAA GTEADMYGQQ PPNESYDQDY TNGEYYGQPP NMAAQDGEN FSDFSSYGPP GTPGYDSYGG QYTASQMSYG EPNSSGTSTP IYGNYDPNAI AMALPNEPYP AWTADSQSPV S IEQIEDIF ...String:
MNTDQQPYQG QTDYTQGPGN GQSQEQDYDQ YGQPLYPSQA DGYYDPNVAA GTEADMYGQQ PPNESYDQDY TNGEYYGQPP NMAAQDGEN FSDFSSYGPP GTPGYDSYGG QYTASQMSYG EPNSSGTSTP IYGNYDPNAI AMALPNEPYP AWTADSQSPV S IEQIEDIF IDLTNRLGFQ RDSMRNMFDH FMVLLDSRSS RMSPDQALLS LHADYIGGDT ANYKKWYFAA QLDMDDEIGF RN MSLGKLS RKARKAKKKN KKAMEEANPE DTEETLNKIE GDNSLEAADF RWKAKMNQLS PLERVRHIAL YLLCWGEANQ VRF TAECLC FIYKCALDYL DSPLCQQRQE PMPEGDFLNR VITPIYHFIR NQVYEIVDGR FVKRERDHNK IVGYDDLNQL FWYP EGIAK IVLEDGTKLI ELPLEERYLR LGDVVWDDVF FKTYKETRTW LHLVTNFNRI WVMHISIFWM YFAYNSPTFY THNYQ QLVD NQPLAAYKWA SCALGGTVAS LIQIVATLCE WSFVPRKWAG AQHLSRRFWF LCIIFGINLG PIIFVFAYDK DTVYST AAH VVAAVMFFVA VATIIFFSIM PLGGLFTSYM KKSTRRYVAS QTFTAAFAPL HGLDRWMSYL VWVTVFAAKY SESYYFL VL PLRDPIRILS TTAMRCTGEY WWGAVLCKVQ PKIVLGLVIA TDFILFFLDT YLWYIIVNTI FSVGKSFYLG ISILTPWR N IFTRLPKRIY SKILATTDME IKYKPKVLIS QVWNAIIISM YREHLLAIDH VQKLLYHQVP SEIEGKRTLR APTFFVSQD DNNFETEFFP RDSEAERRIS FFAQSLSTPI PEPLPVDNMP TFTVLTPHYA ERILLSLREI IREDDQFSRV TLLEYLKQLH PVEWECFVK DTKILAEETA AYEGNENEAE KEDALKSQID DLPFYCIGFK SAAPEYTLRT RIWASLRSQT LYRTISGFMN Y SRAIKLLY RVENPEIVQM FGGNAEGLER ELEKMARRKF KFLVSMQRLA KFKPHELENA EFLLRAYPDL QIAYLDEEPP LT EGEEPRI YSALIDGHCE ILDNGRRRPK FRVQLSGNPI LGDGKSDNQN HALIFYRGEY IQLIDANQDN YLEECLKIRS VLA EFEELN VEQVNPYAPG LRYEEQTTNH PVAIVGAREY IFSENSGVLG DVAAGKEQTF GTLFARTLSQ IGGKLHYGHP DFIN ATFMT TRGGVSKAQK GLHLNEDIYA GMNAMLRGGR IKHCEYYQCG KGRDLGFGTI LNFTTKIGAG MGEQMLSREY YYLGT QLPV DRFLTFYYAH PGFHLNNLFI QLSLQMFMLT LVNLSSLAHE SIMCIYDRNK PKTDVLVPIG CYNFQPAVDW VRRYTL SIF IVFWIAFVPI VVQELIERGL WKATQRFFCH LLSLSPMFEV FAGQIYSSAL LSDLAIGGAR YISTGRGFAT SRIPFSI LY SRFAGSAIYM GARSMLMLLF GTVAHWQAPL LWFWASLSSL IFAPFVFNPH QFAWEDFFLD YRDYIRWLSR GNNQYHRN S WIGYVRMSRA RITGFKRKLV GDESEKAAGD ASRAHRTNLI MAEIIPCAIY AAGCFIAFTF INAQTGVKTT DDDRVNSVL RIIICTLAPI AVNLGVLFFC MGMSCCSGPL FGMCCKKTGS VMAGIAHGVA VIVHIAFFIV MWVLESFNFV RMLIGVVTCI QCQRLIFHC MTALMLTREF KNDHANTAFW TGKWYGKGMG YMAWTQPSRE LTAKVIELSE FAADFVLGHV ILICQLPLII I PKIDKFHS IMLFWLKPSR QIRPPIYSLK QTRLRKRMVK KYCSLYFLVL AIFAGCIIGP AVASAKIHKH IGDSLDGVVH NL FQPINTT NNDTGSQMST YQSHYYTHTP SLKTWSTIK

UniProtKB: 1,3-beta-glucan synthase component FKS1

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Macromolecule #4: nonane

MacromoleculeName: nonane / type: ligand / ID: 4 / Number of copies: 7 / Formula: DD9
Molecular weightTheoretical: 128.255 Da
Chemical component information

ChemComp-DD9:
nonane

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Macromolecule #5: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 5 / Number of copies: 6 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #6: TETRADECANE

MacromoleculeName: TETRADECANE / type: ligand / ID: 6 / Number of copies: 1 / Formula: C14
Molecular weightTheoretical: 198.388 Da
Chemical component information

ChemComp-C14:
TETRADECANE

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Macromolecule #7: HEPTANE

MacromoleculeName: HEPTANE / type: ligand / ID: 7 / Number of copies: 7 / Formula: HP6
Molecular weightTheoretical: 100.202 Da
Chemical component information

ChemComp-HP6:
HEPTANE

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Macromolecule #8: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 8 / Number of copies: 3 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #9: (11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~...

MacromoleculeName: (11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate
type: ligand / ID: 9 / Number of copies: 1 / Formula: XKP
Molecular weightTheoretical: 495.587 Da
Chemical component information

ChemComp-XKP:
(11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 176682
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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