[English] 日本語
Yorodumi
- EMDB-73971: HMG-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-73971
TitleHMG-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
Map dataMap of HMG-CoA synthase 1 (HMGCS1)bound to inhibitor CNP7
Sample
  • Complex: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
    • Protein or peptide: Hydroxymethylglutaryl-CoA synthase, cytoplasmic
  • Ligand: (3S)-1-[(Z)-iminomethyl]-N-({(1P)-3'-[(prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-3-yl}methyl)pyrrolidine-3-carboxamide
Keywordscytosolic protein / metabolic inhibitor / TRANSFERASE
Function / homology
Function and homology information


farnesyl diphosphate biosynthetic process, mevalonate pathway / hydroxymethylglutaryl-CoA synthase / hydroxymethylglutaryl-CoA synthase activity / Cholesterol biosynthesis / acetyl-CoA metabolic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / lipid metabolic process / PPARA activates gene expression / protein homodimerization activity ...farnesyl diphosphate biosynthetic process, mevalonate pathway / hydroxymethylglutaryl-CoA synthase / hydroxymethylglutaryl-CoA synthase activity / Cholesterol biosynthesis / acetyl-CoA metabolic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / lipid metabolic process / PPARA activates gene expression / protein homodimerization activity / cytoplasm / cytosol
Similarity search - Function
Hydroxymethylglutaryl-coenzyme A synthase, active site / Hydroxymethylglutaryl-CoA synthase, eukaryotic / Hydroxymethylglutaryl-coenzyme A synthase active site. / Hydroxymethylglutaryl-coenzyme A synthase, N-terminal / Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain / Hydroxymethylglutaryl-coenzyme A synthase N terminal / Hydroxymethylglutaryl-coenzyme A synthase C terminal / Thiolase-like
Similarity search - Domain/homology
Hydroxymethylglutaryl-CoA synthase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.29 Å
AuthorsAn H / Sun L / de la Cruz MJ / Sen S
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: J Am Chem Soc / Year: 2026
Title: Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer.
Authors: Liang Sun / Sang Ah Yi / Brittany Q Pham / Antoine Mocellin / Sagnik Sen / M Jason de la Cruz / Alban Ordureau / Heeseon An /
Abstract: Comprehensive target validation remains a significant bottleneck in chemical probe development, particularly for covalent inhibitors, where off-target reactivity can lead to toxicity. Using HMG-CoA ...Comprehensive target validation remains a significant bottleneck in chemical probe development, particularly for covalent inhibitors, where off-target reactivity can lead to toxicity. Using HMG-CoA synthase 1 (HMGCS1), an underexplored gatekeeper enzyme in the mevalonate pathway, we demonstrate how integrating orthogonal chemoproteomic methods can provide unbiased, comprehensive insights into the on- and off-target profiles of covalent inhibitors. Our study specifically highlights the limitations of traditional enrichment proteomics in distinguishing high-occupancy binders from low-occupancy binders, and it proposes a solution through a complementary scavenging proteomics approach that analyzes de-enriched fractions, providing target engagement ratios across the proteome. This framework facilitated the development of CNP7, a cyanopyrrolidine that covalently modifies HMGCS1's catalytic cysteine with remarkable selectivity, as assessed by comprehensive chemoproteomics. A 2.29 Å cryo-EM structure reveals how CNP7 engages the catalytic cysteine within HMGCS1's hydrophobic pocket. CNP7 treatment decreases HMG-CoA levels and induces global protein deprenylation within 4 h. Notably, CNP7 exhibits cell line-specific anticancer activity patterns that differ from those of statins, suggesting possible pathway node-specific vulnerabilities. Together, our study offers valuable chemical tools to modulate HMGCS1 activity and presents a framework for the rigorous characterization of covalent inhibitors in chemical biology and drug development.
History
DepositionNov 19, 2025-
Header (metadata) releaseMay 27, 2026-
Map releaseMay 27, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_73971.png

Downloads & links

-
Map

FileDownload / File: emd_73971.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of HMG-CoA synthase 1 (HMGCS1)bound to inhibitor CNP7
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 256 pix.
= 185.6 Å		0.73 Å/pix.
x 256 pix.
= 185.6 Å		0.73 Å/pix.
x 256 pix.
= 185.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0896
Minimum - Maximum-0.72490036 - 1.0494146
Average (Standard dev.)0.000029465458 (±0.031759843)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 185.6 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: Half Map A of HMG-CoA synthase 1 (HMGCS1)bound to inhibitor CNP7

Fileemd_73971_half_map_1.map
AnnotationHalf Map A of HMG-CoA synthase 1 (HMGCS1)bound to inhibitor CNP7
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: Half Map B of HMG-CoA synthase 1 (HMGCS1)bound to inhibitor CNP7

Fileemd_73971_half_map_2.map
AnnotationHalf Map B of HMG-CoA synthase 1 (HMGCS1)bound to inhibitor CNP7
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibit...

EntireName: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
Components
  • Complex: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
    • Protein or peptide: Hydroxymethylglutaryl-CoA synthase, cytoplasmic
  • Ligand: (3S)-1-[(Z)-iminomethyl]-N-({(1P)-3'-[(prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-3-yl}methyl)pyrrolidine-3-carboxamide

-
Supramolecule #1: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibit...

SupramoleculeName: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

-
Macromolecule #1: Hydroxymethylglutaryl-CoA synthase, cytoplasmic

MacromoleculeName: Hydroxymethylglutaryl-CoA synthase, cytoplasmic / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: hydroxymethylglutaryl-CoA synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.290832 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MHHHHHHSSG VDLGTENLYF QSMDVGIVAL EIYFPSQYVD QAELEKYDGV DAGKYTIGLG QAKMGFCTDR EDINSLCMTV VQNLMERNN LSYDCIGRLE VGTETIIDKS KSVKTNLMQL FEESGNTDIE GIDTTNACYG GTAAVFNAVN WIESSSWDGR Y ALVVAGDI ...String:
MHHHHHHSSG VDLGTENLYF QSMDVGIVAL EIYFPSQYVD QAELEKYDGV DAGKYTIGLG QAKMGFCTDR EDINSLCMTV VQNLMERNN LSYDCIGRLE VGTETIIDKS KSVKTNLMQL FEESGNTDIE GIDTTNACYG GTAAVFNAVN WIESSSWDGR Y ALVVAGDI AVYATGNARP TGGVGAVALL IGPNAPLIFE RGLRGTHMQH AYDFYKPDML SEYPIVDGKL SIQCYLSALD RC YSVYCKK IHAQWQKEGN DKDFTLNDFG FMIFHSPYCK LVQKSLARML LNDFLNDQNR DKNSIYSGLE AFGDVKLEDT YFD RDVEKA FMKASSELFS QKTKASLLVS NQNGNMYTSS VYGSLASVLA QYSPQQLAGK RIGVFSYGSG LAATLYSLKV TQDA TPGSA LDKITASLCD LKSRLDSRTG VAPDVFAENM KLREDTHHLV NYIPQGSIDS LFEGTWYLVR VDEKHRRTYA RRP

UniProtKB: Hydroxymethylglutaryl-CoA synthase, cytoplasmic

-
Macromolecule #2: (3S)-1-[(Z)-iminomethyl]-N-({(1P)-3'-[(prop-2-yn-1-yl)carbamoyl][...

MacromoleculeName: (3S)-1-[(Z)-iminomethyl]-N-({(1P)-3'-[(prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-3-yl}methyl)pyrrolidine-3-carboxamide
type: ligand / ID: 2 / Number of copies: 2 / Formula: A1C1C
Molecular weightTheoretical: 388.462 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

-
Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

+
Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

2p8u

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.29 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 589925
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
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