9R0E

Structure of the human heterotetrameric cis-prenyltransferase complex harboring NgBR-S249T in complex with magnesium, FsPP and IPP

9R0E の概要

• エントリーDOI: 10.2210/pdb9r0e/pdb
• 分子名称: Dehydrodolichyl diphosphate synthase complex subunit DHDDS, Dehydrodolichyl diphosphate synthase complex subunit NUS1, 3-METHYLBUT-3-ENYL TRIHYDROGEN DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: cis-prenyltransferase, dolichol, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63663.98

構造登録者

Giladi, M.,Haitin, Y. (登録日: 2025-04-24, 公開日: 2025-10-29, 最終更新日: 2025-12-10)

主引用文献

Giladi, M.,Kredi, S.,Guardiani, C.,Aviram, L.,Vankova, P.,Gaizinger, Y.,Man, P.,Giacomello, A.,Haitin, Y.
Structural mechanisms of allosteric regulation in the human cis-prenyltransferase complex.
Nat Commun, 16:10786-10786, 2025

PubMed Abstract: Human cis-prenyltransferase (hcis-PT) synthesizes long-chain isoprenoids essential for N-linked protein glycosylation. This heteromeric complex comprises the catalytic subunit DHDDS and the regulatory Nogo-B receptor (NgBR). Although NgBR dramatically enhances DHDDS activity, the molecular basis for this allosteric regulation remains unclear. Here, we combined crystallography, hydrogen-deuterium exchange mass spectrometry (HDX-MS), molecular dynamics simulations, and network analysis to uncover the structural dynamics and communication pathways within hcis-PT. By solving the apo structure of hcis-PT, we reveal only a localized flexibility at the active site and the NgBR C-terminus. However, HDX-MS demonstrated widespread substrate-induced stabilization, particularly at the NgBR βD-βE loop, highlighting it as an allosteric hub. Functional mutagenesis scanning identified NgBR as critical for enzymatic activity, independent of structural perturbations. Network analysis of MD simulations pinpointed this residue as a central node in inter-subunit communication, with perturbations disrupting downstream allosteric pathways, altering enzymatic activity. Our findings reveal a dynamic regulatory network centered at the inter-subunit interface, wherein specific NgBR residues modulate DHDDS activity through allosteric signaling. This work elucidates a conserved mechanism of subunit coordination in long-chain cis-prenyltransferases and suggests avenues for therapeutic targeting of hcis-PT-related disorders.

PubMed: 41315348
DOI: 10.1038/s41467-025-65833-6

実験手法

X-RAY DIFFRACTION (2.82 Å)