9ZAW

HMG-CoA synthase 1 (HMGCS1) bound to inhibitor compound CNP7

This is a non-PDB format compatible entry.

Summary for 9ZAW

• Entry DOI: 10.2210/pdb9zaw/pdb
• EMDB information: 73971
• Descriptor: Hydroxymethylglutaryl-CoA synthase, cytoplasmic, (3S)-1-[(Z)-iminomethyl]-N-({(1P)-3'-[(prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-3-yl}methyl)pyrrolidine-3-carboxamide (2 entities in total)
• Functional Keywords: cytosolic protein, metabolic inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 107358.59

Authors

An, H.,Sun, L.,de la Cruz, M.J.,Sen, S. (deposition date: 2025-11-19, release date: 2026-05-27, Last modification date: 2026-06-03)

Primary citation

Sun, L.,Yi, S.A.,Pham, B.Q.,Mocellin, A.,Sen, S.,de la Cruz, M.J.,Ordureau, A.,An, H.
Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer.
J.Am.Chem.Soc., 148:20705-20719, 2026

PubMed 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 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.

PubMed: 42127206
DOI: 10.1021/jacs.6c02556

Experimental method

ELECTRON MICROSCOPY (2.29 Å)