6FCL

Crystal Structure of Human APRT wild type in complex with AMP

Summary for 6FCL

• Entry DOI: 10.2210/pdb6fcl/pdb
• Related: 6FCH 6FCI 6FD4 6FD5 6FD6
• Descriptor: Adenine phosphoribosyltransferase, ADENOSINE MONOPHOSPHATE (3 entities in total)
• Functional Keywords: rossman fold, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 39549.35

Authors

Nioche, P.,Huyet, J.,Ozeir, M. (deposition date: 2017-12-20, release date: 2018-08-15, Last modification date: 2024-01-17)

Primary citation

Huyet, J.,Ozeir, M.,Burgevin, M.C.,Pinson, B.,Chesney, F.,Remy, J.M.,Siddiqi, A.R.,Lupoli, R.,Pinon, G.,Saint-Marc, C.,Gibert, J.F.,Morales, R.,Ceballos-Picot, I.,Barouki, R.,Daignan-Fornier, B.,Olivier-Bandini, A.,Auge, F.,Nioche, P.
Structural Insights into the Forward and Reverse Enzymatic Reactions in Human Adenine Phosphoribosyltransferase.
Cell Chem Biol, 25:666-676.e4, 2018

PubMed Abstract: Phosphoribosyltransferases catalyze the displacement of a PRPP α-1'-pyrophosphate to a nitrogen-containing nucleobase. How they control the balance of substrates/products binding and activities is poorly understood. Here, we investigated the human adenine phosphoribosyltransferase (hAPRT) that produces AMP in the purine salvage pathway. We show that a single oxygen atom from the Tyr105 side chain is responsible for selecting the active conformation of the 12 amino acid long catalytic loop. Using in vitro, cellular, and in crystallo approaches, we demonstrated that Tyr105 is key for the fine-tuning of the kinetic activity efficiencies of the forward and reverse reactions. Together, our results reveal an evolutionary pressure on the strictly conserved Tyr105 and on the dynamic motion of the flexible loop in phosphoribosyltransferases that is essential for purine biosynthesis in cells. These data also provide the framework for designing novel adenine derivatives that could modulate, through hAPRT, diseases-involved cellular pathways.

PubMed: 29576532
DOI: 10.1016/j.chembiol.2018.02.011

Experimental method

X-RAY DIFFRACTION (1.5 Å)