4EQG

Crystal structure of histidine triad nucleotide-binding protein 1 (HINT1) from human complexed with Ala-AMS

Summary for 4EQG

• Entry DOI: 10.2210/pdb4eqg/pdb
• Related: 4EQE 4EQH
• Descriptor: Histidine triad nucleotide-binding protein 1, '5'-O-(N-(L-ALANYL)-SULFAMOYL)ADENOSINE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: hit domain, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49773
• Total number of polymer chains: 2
• Total formula weight: 28704.03

Authors

Wang, J.,Fang, P.,Guo, M. (deposition date: 2012-04-18, release date: 2012-05-02, Last modification date: 2023-09-13)

Primary citation

Wang, J.,Fang, P.,Schimmel, P.,Guo, M.
Side chain independent recognition of aminoacyl adenylates by the hint1 transcription suppressor.
J.Phys.Chem.B, 116:6798-6805, 2012

PubMed Abstract: Human Hint1 suppresses specific gene transcription by interacting with the transcription factor MITF in mast cells. Hint1 activity is connected to lysyl-tRNA synthetase (LysRS), a member of the universal aminoacyl tRNA synthetase family that catalyzes specific aminoacylation of their cognate tRNAs, through an aminoacyl adenylate (aa-AMP) intermediate. During immune activation, LysRS produces a side-product diadenosine tetraphosphate (Ap(4)A) from the condensation of Lys-AMP with ATP. The pleiotropic signaling molecule Ap(4)A then binds Hint1 to promote activation of MITF-target gene transcription. Earlier work showed that Hint1 can also bind and hydrolyze Lys-AMP, possibly to constrain Ap(4)A production. Because Ap(4)A can result from condensation of other aa-AMP's with ATP, the specificity of the Hint1 aa-AMP-hydrolysis activity is of interest. Here we show that Hint1 has broad specificity for adenylate hydrolysis, whose structural basis we revealed through high-resolution structures of Hint1 in complex with three different aa-AMP analogues. Hint1 recognizes only the common main chain of the aminoacyl moiety, and has no contact with the aa side chain. The α-amino group is anchored by a cation-pi interaction with Trp123 at the C-terminus of Hint1. These results reveal the structural basis for the remarkable adenylate surveillance activity of Hint1, to potentially control Ap(4)A levels in the cell.

PubMed: 22329685
DOI: 10.1021/jp212457w

Experimental method

X-RAY DIFFRACTION (1.52 Å)