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Structure paper

TitleStructure of mitochondrial pyruvate carrier and its inhibition mechanism.
Journal, issue, pagesNature, Vol. 641, Issue 8061, Page 250-257, Year 2025
Publish dateMar 5, 2025
AuthorsZheng He / Jianxiu Zhang / Yan Xu / Eve J Fine / Carl-Mikael Suomivuori / Ron O Dror / Liang Feng /
PubMed AbstractThe mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial ...The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
External linksNature / PubMed:40044865 / PubMed Central
MethodsEM (single particle)
Resolution2.73 - 3.35 Å
Structure data

48441

9mnw

EMDB-48441: Cryo-EM structure of membrane transporter with inhibitor G
PDB-9mnw: Cryo-EM structure of human MPC in complex with GW604714
Method: EM (single particle) / Resolution: 3.35 Å

48442

9mnx

EMDB-48442, PDB-9mnx:
Cryo-EM structure of human MPC in complex with UK5099 in LMNG
Method: EM (single particle) / Resolution: 3.11 Å

48443

9mny

EMDB-48443, PDB-9mny:
Cryo-EM structure of human MPC with pyruvate
Method: EM (single particle) / Resolution: 2.78 Å

48444

9mnz

EMDB-48444, PDB-9mnz:
Cryo-EM structure of human MPC in complex with UK5099 in nanodiscs
Method: EM (single particle) / Resolution: 2.73 Å

48445

9mo0

EMDB-48445, PDB-9mo0:
Cryo-EM structure of human MPC in complex with AKOS005153046
Method: EM (single particle) / Resolution: 2.83 Å

Chemicals

PDB-1bm8:
DNA-BINDING DOMAIN OF MBP1

ChemComp-I2R:
(E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid

ChemComp-PYR:
PYRUVIC ACID

PDB-1il4:
STRUCTURE OF RICIN A CHAIN BOUND WITH INHIBITOR 9-DEAZAGUANINE

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • synthetic construct (others)
  • escherichia coli (E. coli)
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM/INHIBITOR / Membrane transporter / TRANSPORT PROTEIN-IMMUNE SYSTEM-INHIBITOR complex / TRANSPORT PROTEIN/IMMUNE SYSTEM / TRANSPORT PROTEIN-IMMUNE SYSTEM complex

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