7x7s | pdb_00007x7s
Solution structure of human adenylate kinase 1 (hAK1)
Structural highlights
DiseaseKAD1_HUMAN Defects in AK1 are the cause of hemolytic anemia due to adenylate kinase deficiency (HAAKD) [MIM:612631.[1] [2] [3] FunctionKAD1_HUMAN Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Small ubiquitous enzyme involved in energy metabolism and nucleotide synthesis that is essential for maintenance and cell growth. Publication Abstract from PubMedHuman adenylate kinase 1 (hAK1) plays a vital role in the energetic and metabolic regulation of cell life, and impaired functions of hAK1 are closely associated with many diseases. In the presence of Mg(2+) ions, hAK1 in vivo can catalyze two ADP molecules into one ATP and one AMP molecule, activating the downstream AMP signaling. The ADP-binding also initiates AK1 transition from an open conformation to a closed conformation. However, how substrate binding triggers the conformational transition of hAK1 is still unclear, and the underlying molecular mechanisms remain elusive. Herein, we determined the solution structure of apo-hAK1 and its key residues for catalyzing ADP, and characterized backbone dynamics characteristics of apo-hAK1 and hAK1-Mg(2+)-ADP complex (holo-hAK1) using NMR relaxation experiments. We found that ADP was primarily bound to a cavity surrounded by the LID, NMP, and CORE domains of hAK1, and identified several critical residues for hAK1 catalyzing ADP including G16, G18, G20, G22, T39, G40, R44, V67, D93, G94, D140, and D141. Furthermore, we found that apo-hAK1 adopts an open conformation with significant ps-ns internal mobility, and Mg(2+)-ADP binding triggered conformational transition of hAK1 by suppressing the ps-ns internal motions of alpha(3)alpha(4) in the NMP domain and alpha(7)alpha(8) in the LID domain. Both alpha(3)alpha(4) and alpha(7)alpha(8) fragments became more rigid so as to fix the substrate, while the catalyzing center of hAK1 experiences promoted micros-ms conformational exchange, potentially facilitating catalysis reaction and conformational transition. Our results provide the structural basis of hAK1 catalyzing ADP into ATP and AMP, and disclose the driving force that triggers the conformational transition of hAK1, which will deepen understanding of the molecular mechanisms of hAK1 functions. ADP-Induced Conformational Transition of Human Adenylate Kinase 1 Is Triggered by Suppressing Internal Motion of alpha(3)alpha(4) and alpha(7)alpha(8) Fragments on the ps-ns Timescale.,Guo C, Zhang H, Lin W, Chen H, Chang T, Wu Z, Yu J, Lin D Biomolecules. 2022 May 6;12(5):671. doi: 10.3390/biom12050671. PMID:35625598[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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