scholarly journals Crystal structure of glutamate dehydrogenase 2, a positively selected novel human enzyme involved in brain biology and cancer pathophysiology

2021 ◽  
Author(s):  
Christina Dimovasili ◽  
Vasiliki E. Fadouloglou ◽  
Aikaterini Kefala ◽  
Mary Providaki ◽  
Dina Kotsifaki ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutamate Dehydrogenase ◽  
Human Enzyme

scholarly journals Crystal structure of a chimaeric bacterial glutamate dehydrogenase

2016 ◽  
Vol 72 (6) ◽  
pp. 462-466 ◽  
Author(s):  
Tânia Oliveira ◽  
Michael A. Sharkey ◽  
Paul C. Engel ◽  
Amir R. Khan
Keyword(s):  
Crystal Structure ◽  
Glutamate Dehydrogenase ◽  
Rigid Bodies ◽  
Nucleotide Binding Domain ◽  
Oxidative Deamination ◽  
E Coli ◽  
Cofactor Binding ◽  
Signature Sequences ◽  
Clostridium Symbiosum ◽  
Domain I

Glutamate dehydrogenases (EC 1.4.1.2–4) catalyse the oxidative deamination of L-glutamate to α-ketoglutarate using NAD(P)+as a cofactor. The bacterial enzymes are hexameric, arranged with 32 symmetry, and each polypeptide consists of an N-terminal substrate-binding segment (domain I) followed by a C-terminal cofactor-binding segment (domain II). The catalytic reaction takes place in the cleft formed at the junction of the two domains. Distinct signature sequences in the nucleotide-binding domain have been linked to the binding of NAD+versusNADP+, but they are not unambiguous predictors of cofactor preference. In the absence of substrate, the two domains move apart as rigid bodies, as shown by the apo structure of glutamate dehydrogenase fromClostridium symbiosum. Here, the crystal structure of a chimaeric clostridial/Escherichia colienzyme has been determined in the apo state. The enzyme is fully functional and reveals possible determinants of interdomain flexibility at a hinge region following the pivot helix. The enzyme retains the preference for NADP+cofactor from the parentE. colidomain II, although there are subtle differences in catalytic activity.

scholarly journals Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization

2004 ◽  
Vol 279 (19) ◽  
pp. 20480-20489 ◽  
Author(s):  
Kallol Ray ◽  
Christina S. Hines ◽  
Jerry Coll-Rodriguez ◽  
David W. Rodgers
Keyword(s):  
Crystal Structure ◽  
Active Site ◽  
Nuclear Import ◽  
Bioactive Peptides ◽  
Protein Protein Interaction ◽  
Human Enzyme ◽  
Deep Channel ◽  
Thimet Oligopeptidase ◽  
Degree Of Order ◽  
Insight Into

Thimet oligopeptidase (TOP) is a zinc metallopeptidase that metabolizes a number of bioactive peptides and degrades peptides released by the proteasome, limiting antigenic presentation by MHC class I molecules. We present the crystal structure of human TOP at 2.0-Å resolution. The active site is located at the base of a deep channel that runs the length of the elongated molecule, an overall fold first seen in the closely related metallopeptidase neurolysin. Comparison of the two related structures indicates hinge-like flexibility and identifies elements near one end of the channel that adopt different conformations. Relatively few of the sequence differences between TOP and neurolysin map to the proposed substrate-binding site, and four of these variable residues may account for differences in substrate specificity. In addition, a loop segment (residues 599-611) in TOP differs in conformation and degree of order from the corresponding neurolysin loop, suggesting it may also play a role in activity differences. Cysteines thought to mediate covalent oligomerization of rat TOP, which can inactivate the enzyme, are found to be surface-accessible in the human enzyme, and additional cysteines (residues 321,350, and 644) may also mediate multimerization in the human homolog. Disorder in the N terminus of TOP indicates it may be involved in subcellular localization, but a potential nuclear import element is found to be part of a helix and, therefore, unlikely to be involved in transport. A large acidic patch on the surface could potentially mediate a protein-protein interaction, possibly through formation of a covalent linkage.

scholarly journals Structural studies on leukotriene A4 hydrolases reveal their catalytic mechanism

2014 ◽  
Vol 70 (a1) ◽  
pp. C413-C413
Author(s):  
Mahmudul Hasan ◽  
Agnes Rinaldo-Matthis ◽  
Marjolein Thunnissen
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Active Site ◽  
Epoxide Hydrolase ◽  
Aminopeptidase Activity ◽  
Molecular Architecture ◽  
Inhibitor Binding ◽  
Induced Fit ◽  
Human Enzyme ◽  
Leukotriene A4

Vertebrate leukotriene A4 hydrolases are zinc metalloenzymes with an epoxide hydrolase and aminopeptidase activity belonging to the M1 family of aminopeptidases. Bestatin, an amino peptidase inhibitor, can inhibit both the activities. The human enzyme produces LTB4, a powerful mediator of inflammation and is implicated in a wide variety of rheumatoid diseases. The yeast homolog scLTA4H contains only a rudimentary epoxide hydrolase activity. Both the structure of the human enzyme and recently the structure of scLTA4H and have been solved to investigate the molecular architecture of the active site both with and without inhibitor Bestatin. The structure of scLTA4H shows large domain movements creating an open active site. In the human enzyme the LTA4 binding side is a narrow hydrophobic channel. Upon inhibitor a domain shifts occurs and the final binding pocket is formed. The fact that scLTA4H displays this induced fit is an interesting observation. Many members of the M1 family seem to display a certain degree of induced fit, a feature, which however, has never been observed for humLTA4H. Our recent solution SAXS studies show that humLTA4H does not make any conformational changes upon inhibitor binding which is consistent with our previous speculation that it functions by a lock and key mechanism rather than induced fit and is better suited to supply the protective and precise environment for hydrolysis of LTA4 into LTB4. On the other hand Xenopus LTA4H shows conformational change in the higher/wide angular region ( >1 nm-1) and decrease in Porod volume of approximately 20 nm3 but no change in Rg or Dmax was observed. It is also observed that like in crystal structure Xenopus LTA4H forms dimer in solution. Similarly scLTA4H forms dimer in solution, which is unlike the crystal structure, and also make conformational changes upon inhibitor binding. Taken together, Xenopus and scLTA4H makes more compact form, with decrease in flexibility, to perform it's catalytic action.

scholarly journals Crystal structure of NAD+-dependent Peptoniphilus asaccharolyticus glutamate dehydrogenase reveals determinants of cofactor specificity

2012 ◽  
Vol 177 (2) ◽  
pp. 543-552 ◽  
Author(s):  
Tânia Oliveira ◽  
Santosh Panjikar ◽  
John B. Carrigan ◽  
Muaawia Hamza ◽  
Michael A. Sharkey ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutamate Dehydrogenase ◽  
Cofactor Specificity

Crystal structure of glutamate dehydrogenase 3 from Candida albicans

2021 ◽  
Vol 570 ◽  
pp. 15-20
Author(s):  
Na Li ◽  
Wenfeng Wang ◽  
Xue Zeng ◽  
Mingjie Liu ◽  
Mengyu Li ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Candida Albicans ◽  
Glutamate Dehydrogenase

scholarly journals Crystal structure of the 2-iminoglutarate-bound complex of glutamate dehydrogenase fromCorynebacterium glutamicum

FEBS Letters ◽  
2017 ◽  
Vol 591 (11) ◽  
pp. 1611-1622 ◽  
Author(s):  
Takeo Tomita ◽  
Lulu Yin ◽  
Shugo Nakamura ◽  
Saori Kosono ◽  
Tomohisa Kuzuyama ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutamate Dehydrogenase

scholarly journals The crystal structure of Escherichia coli purine nucleoside phosphorylase: a comparison with the human enzyme reveals a conserved topology

Structure ◽  
1997 ◽  
Vol 5 (10) ◽  
pp. 1373-1383 ◽  
Author(s):  
Chen Mao ◽  
William J Cook ◽  
Min Zhou ◽  
George W Koszalka ◽  
Thomas A Krenitsky ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Escherichia Coli ◽  
Purine Nucleoside Phosphorylase ◽  
Purine Nucleoside ◽  
Nucleoside Phosphorylase ◽  
Human Enzyme
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