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- EMDB-76894: Cryo-EM structure of hexameric apo human K293st geranylgeranyl di... -

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Basic information

Entry
Database: EMDB / ID: EMD-76894
TitleCryo-EM structure of hexameric apo human K293st geranylgeranyl diphosphate synthase
Map dataFlipped raw map used for fitting the atomic model
Sample
  • Complex: Cryo-EM structure of hexameric apo human K293st geranylgeranyl diphosphate synthase
    • Protein or peptide: Geranylgeranyl pyrophosphate synthase
KeywordsGeranylgeranyl pyrophosphate synthase / geranylgeranyl diphosphate / geranylgeranyl pyrophosphate / apo / prenyltransferase / isoprenyl / TRANSFERASE
Function / homology
Function and homology information


isoprenoid metabolic process / geranylgeranyl diphosphate synthase / geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / Transferases; Transferring alkyl or aryl groups, other than methyl groups / (2E,6E)-farnesyl diphosphate synthase / Lanosterol biosynthesis / geranylgeranyl diphosphate synthase activity / geranylgeranyl diphosphate biosynthetic process / trans, trans-farnesyl diphosphate biosynthetic process ...isoprenoid metabolic process / geranylgeranyl diphosphate synthase / geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / Transferases; Transferring alkyl or aryl groups, other than methyl groups / (2E,6E)-farnesyl diphosphate synthase / Lanosterol biosynthesis / geranylgeranyl diphosphate synthase activity / geranylgeranyl diphosphate biosynthetic process / trans, trans-farnesyl diphosphate biosynthetic process / isoprenoid biosynthetic process / dimethylallyltranstransferase activity / (2E,6E)-farnesyl diphosphate synthase activity / Activation of gene expression by SREBF (SREBP) / Z disc / perinuclear region of cytoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Polyprenyl synthases signature 1. / Polyprenyl synthases signature 2. / Polyprenyl synthetase, conserved site / Polyprenyl synthetase / Polyprenyl synthetase / Isoprenoid synthase domain superfamily
Similarity search - Domain/homology
Geranylgeranyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / negative staining / Resolution: 2.3 Å
AuthorsPham AC / Borgstahl EO
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA25862 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA036727 United States
Other governmentP200A210032 United States
CitationJournal: Biochemistry / Year: 2026
Title: Mapping Ligand-Induced Conformational Changes during the Enzymatic Cycle of Human Geranylgeranyl Diphosphate Synthase.
Authors: Andrew C Pham / Lucas R Struble / Lasini Amunugama / Jared B Shaw / Timothy R Stachowski / Sarah A Holstein / Gloria E O Borgstahl /
Abstract: Geranylgeranyl diphosphate synthase (GGDPS) catalyzes the condensation reaction between two isoprenoid substrates: farnesyl diphosphate (FDP) and isopentenyl pyrophosphate (IPP), to form ...Geranylgeranyl diphosphate synthase (GGDPS) catalyzes the condensation reaction between two isoprenoid substrates: farnesyl diphosphate (FDP) and isopentenyl pyrophosphate (IPP), to form geranylgeranyl diphosphate (GGDP). Due to the flexible nature of the GGDPS active site and its capacity to bind multiple ligands during the reaction coordinate, understanding the structural changes that enable it to accommodate different ligands and catalyze the reaction is essential. While structures exist of substrate and product-bound GGDPS, a lack of high-resolution apo or Mg2+-only structures prevents complete understanding of the enzyme active site. Here, we report apo and Mg2+-only structures of human GGDPS, investigating the key differences between them and published GGDPS structures relating to the enzymatic cycle. A crystal structure resolved to 1.82 Å, the highest-resolution structure of human GGDPS to date, contains five product-bound subunits and one Mg2+-only subunit. The first cryo-EM structure of apo GGDPS is also reported, which exhibited an open hexamer conformation. Comparing the Mg2+-only and apo structures shows that the active site is posed and ready to bind Mg2+ without significant conformational changes. Comparing Mg2+-only to structures with either of the substrates or product bound, we observe changes in residues that actively obstruct or encourage the binding of certain ligands. We also propose an enzymatic mechanism for the structural states of GGDPS and highlight the possibility of Asp188 as the general base in the condensation reaction. These findings enhance our understanding of GGDPS ligand binding, which will improve the knowledge base for rational, structure-based design of future GGDPS inhibitors.
History
DepositionApr 24, 2026-
Header (metadata) releaseOct 28, 2026-
Map releaseOct 28, 2026-
UpdateOct 28, 2026-
Current statusOct 28, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76894.png

Downloads & links

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Map

FileDownload / File: emd_76894.map.gz / Format: CCP4 / Size: 266.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFlipped raw map used for fitting the atomic model
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 412 pix.
= 300.595 Å		0.73 Å/pix.
x 412 pix.
= 300.595 Å		0.73 Å/pix.
x 412 pix.
= 300.595 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7296 Å
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Contour LevelBy AUTHOR: 0.09
Minimum - Maximum-0.20840426 - 0.56452274
Average (Standard dev.)0.00044644746 (±0.01189582)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions412412412
Spacing412412412
CellA=B=C: 300.5952 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_76894_msk_1.map
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Additional map: Sharpened map

Fileemd_76894_additional_1.map
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Additional map: Raw un-flipped map

Fileemd_76894_additional_2.map
AnnotationRaw un-flipped map
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Additional map: Flipped sharpened map used for fitting the atomic model

Fileemd_76894_additional_3.map
AnnotationFlipped sharpened map used for fitting the atomic model
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Additional map: Raw UN-flipped half map B

Fileemd_76894_additional_4.map
AnnotationRaw UN-flipped half map B
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Additional map: Raw UN-flipped half map A

Fileemd_76894_additional_5.map
AnnotationRaw UN-flipped half map A
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Half map: Raw flipped half map A for use in modeling

Fileemd_76894_half_map_1.map
AnnotationRaw flipped half map A for use in modeling
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Half map: Raw flipped half map B for use in modeling

Fileemd_76894_half_map_2.map
AnnotationRaw flipped half map B for use in modeling
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Sample components

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Entire : Cryo-EM structure of hexameric apo human K293st geranylgeranyl di...

EntireName: Cryo-EM structure of hexameric apo human K293st geranylgeranyl diphosphate synthase
Components
  • Complex: Cryo-EM structure of hexameric apo human K293st geranylgeranyl diphosphate synthase
    • Protein or peptide: Geranylgeranyl pyrophosphate synthase

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Supramolecule #1: Cryo-EM structure of hexameric apo human K293st geranylgeranyl di...

SupramoleculeName: Cryo-EM structure of hexameric apo human K293st geranylgeranyl diphosphate synthase
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 203.52 KDa

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Macromolecule #1: Geranylgeranyl pyrophosphate synthase

MacromoleculeName: Geranylgeranyl pyrophosphate synthase / type: protein_or_peptide / ID: 1 / Details: Removal of KMFKEENE at C-terminus / Number of copies: 6 / Enantiomer: LEVO
EC number: Transferases; Transferring alkyl or aryl groups, other than methyl groups
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.964738 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SMEKTQETVQ RILLEPYKYL LQLPGKQVRT KLSQAFNHWL KVPEDKLQII IEVTEMLHNA SLLIDDIEDN SKLRRGFPVA HSIYGIPSV INSANYVYFL GLEKVLTLDH PDAVKLFTRQ LLELHQGQGL DIYWRDNYTC PTEEEYKAMV LQKTGGLFGL A VGLMQLFS ...String:
SMEKTQETVQ RILLEPYKYL LQLPGKQVRT KLSQAFNHWL KVPEDKLQII IEVTEMLHNA SLLIDDIEDN SKLRRGFPVA HSIYGIPSV INSANYVYFL GLEKVLTLDH PDAVKLFTRQ LLELHQGQGL DIYWRDNYTC PTEEEYKAMV LQKTGGLFGL A VGLMQLFS DYKEDLKPLL NTLGLFFQIR DDYANLHSKE YSENKSFCED LTEGKFSFPT IHAIWSRPES TQVQNILRQR TE NIDIKKY CVHYLEDVGS FEYTRNTLKE LEAKAYKQID ARGGNPELVA LVKHLS

UniProtKB: Geranylgeranyl pyrophosphate synthase

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Experimental details

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Structure determination

Methodnegative staining, cryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
100.0 mMNaClsodium chloride
10.0 mMC8H18N2O4SHEPES
0.5 mMC9H15O6PTCEP
1.0 mMMgCl2magnesium chloride
StainingType: NEGATIVE / Material: NanoVan
Details: Samples in solution (0.1 mg/mL) were air dried onto silicone monoxide treated, formvar coated grids and subsequently stained with NanoVan.
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 47.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 165000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.5) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6r4v

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5) / Number images used: 1142326
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.5)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6r4v


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-12zr:
Cryo-EM structure of hexameric apo human K293st geranylgeranyl diphosphate synthase

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