scholarly journals Crystal structures of FolM alternative dihydrofolate reductase 1 from Brucella suis and Brucella canis

2022 ◽  
Vol 78 (1) ◽  
Author(s):  
Imani Porter ◽  
Trinity Neal ◽  
Zion Walker ◽  
Dylan Hayes ◽  
Kayla Fowler ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Structural Genomics ◽  
Structural Similarity ◽  
Biological Warfare ◽  
Infectious Agents ◽  
Sequence Identity ◽  
Brucella Canis ◽  
Brucella Suis ◽  
Dihydrofolate Reductases ◽  
Therapeutic Development

Members of the bacterial genus Brucella cause brucellosis, a zoonotic disease that affects both livestock and wildlife. Brucella are category B infectious agents that can be aerosolized for biological warfare. As part of the structural genomics studies at the Seattle Structural Genomics Center for Infectious Disease (SSGCID), FolM alternative dihydrofolate reductases 1 from Brucella suis and Brucella canis were produced and their structures are reported. The enzymes share ∼95% sequence identity but have less than 33% sequence identity to other homologues with known structure. The structures are prototypical NADPH-dependent short-chain reductases that share their highest tertiary-structural similarity with protozoan pteridine reductases, which are being investigated for rational therapeutic development.

scholarly journals Crystal structure of chorismate mutase fromBurkholderia phymatum

2018 ◽  
Vol 74 (4) ◽  
pp. 187-192 ◽  
Author(s):  
Oluwatoyin A. Asojo ◽  
Sandhya Subramanian ◽  
Jan Abendroth ◽  
Ilyssa Exley ◽  
Donald D. Lorimer ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Drug Development ◽  
Structural Genomics ◽  
Active Site ◽  
Chorismate Mutase ◽  
Biological Warfare ◽  
Beneficial Bacteria ◽  
Sequence Identity ◽  
Resolution Structure

The bacteriumBurkholderia phymatumis a promiscuous symbiotic nitrogen-fixating bacterium that belongs to one of the largest groups of Betaproteobacteria. OtherBurkholderiaspecies are known to cause disease in plants and animals, and some are potential agents for biological warfare. Structural genomics efforts include characterizing the structures of enzymes from pathways that can be targeted for drug development. As part of these efforts, chorismate mutase fromB. phymatumwas produced and crystallized, and a 1.95 Å resolution structure is reported. This enzyme shares less than 33% sequence identity with other homologs of known structure. There are two classes of chorismate mutase: AroQ and AroH. The bacterial subclass AroQγ has reported roles in virulence. Chorismate mutase fromB. phymatumhas the prototypical AroQγ topology and retains the characteristic chorismate mutase active site. This suggests that substrate-based chorismate mutase inhibitors will not be specific and are likely to affect beneficial bacteria such asB. phymatum.

Structural Similarity between the Prion Domain of HET-s and a Homologue Can Explain Amyloid Cross-Seeding in Spite of Limited Sequence Identity

2010 ◽  
Vol 402 (2) ◽  
pp. 311-325 ◽  
Author(s):  
Christian Wasmer ◽  
Agnes Zimmer ◽  
Raimon Sabaté ◽  
Alice Soragni ◽  
Sven J. Saupe ◽  
...  
Keyword(s):  
Structural Similarity ◽  
Sequence Identity ◽  
Limited Sequence

Data Integration Through Protein Ontology

2011 ◽  
pp. 106-122
Author(s):  
Amandeep S. Sidhu ◽  
Tharam S. Dillon ◽  
Elizabeth Chang
Keyword(s):  
Hierarchical Classification ◽  
Structural Similarity ◽  
Protein Annotation ◽  
Functional Identification ◽  
Sequence Identity ◽  
Alternative Protein ◽  
Traditional Approaches ◽  
High Degree ◽  
Keyword Searches

Traditional approaches to integrate protein data generally involved keyword searches, which immediately excludes unannotated or poorly annotated data. An alternative protein annotation approach is to rely on sequence identity, or structural similarity, or functional identification. Some proteins have high degree of sequence identity, or structural similarity, or similarity in functions that are unique to members of that family alone. Consequently, this approach can’t be generalized to integrate the protein data. Clearly, these traditional approaches have limitations in capturing and integrating data for Protein Annotation. For these reasons, we have adopted an alternative method that does not rely on keywords or similarity metrics, but instead uses ontology. In this chapter we discuss conceptual framework of Protein Ontology that has a hierarchical classification of concepts represented as classes, from general to specific; a list of attributes related to each concept, for each class; a set of relations between classes to link concepts in ontology in more complicated ways then implied by the hierarchy, to promote reuse of concepts in the ontology; and a set of algebraic operators for querying protein ontology instances.

scholarly journals Crystal Structures of Klebsiella pneumoniae Dihydrofolate Reductase Bound to Propargyl-Linked Antifolates Reveal Features for Potency and Selectivity

2014 ◽  
Vol 58 (12) ◽  
pp. 7484-7491 ◽  
Author(s):  
Kristen M. Lamb ◽  
Michael N. Lombardo ◽  
Jeremy Alverson ◽  
Nigel D. Priestley ◽  
Dennis L. Wright ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Crystal Structures ◽  
Dihydrofolate Reductase ◽  
Next Generation ◽  
Gram Negative ◽  
Content Type ◽  
Resistant Species ◽  
Loop Conformations ◽  
The Family ◽  
Dihydrofolate Reductases

ABSTRACTResistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the familyEnterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, includingKlebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains ofK. pneumoniae, some with MIC values of 1 μg/ml. In order to further the design of potent and selective antifolates against members of theEnterobacteriaceae, we determined the first crystal structures ofK. pneumoniaeDHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity.

Heterogeneity in the specific activity and methotrexate sensitivity of dihydrofolate reductase from blast cells of acute myelogenous leukemia patients.

1985 ◽  
Vol 3 (11) ◽  
pp. 1545-1552 ◽  
Author(s):  
S Dedhar ◽  
D Hartley ◽  
D Fitz-Gibbons ◽  
G Phillips ◽  
J H Goldie
Keyword(s):  
Dihydrofolate Reductase ◽  
Acute Myelogenous Leukemia ◽  
Specific Activity ◽  
Reductase Activity ◽  
Myelogenous Leukemia ◽  
Mechanisms Of Resistance ◽  
Clinical Resistance ◽  
Dihydrofolate Reductases ◽  
Acute Myelogenous ◽  
Blast Cells

Dihydrofolate reductase activity was found to be highly heterogeneous in terms of its specific activity and methotrexate sensitivity in the blast cells of patients with acute myelogenous leukemia. None of the patients had previously been treated with methotrexate (MTX). The blast cells of four of 12 patients studied contained methotrexate-insensitive forms of dihydrofolate reductase, and the blast cells of three (distinct from the four mentioned previously) of the 12 had significantly higher dihydrofolate reductase activities than the rest. The presence of MTX-insensitive dihydrofolate reductases and high levels of enzyme activity represent intrinsic mechanisms of resistance and may explain the apparent clinical resistance of acute myelogenous leukemia to methotrexate.

scholarly journals Plasmid-mediated trimethoprim-resistance in Staphylococcus aureus. Characterization of the first gram-positive plasmid dihydrofolate reductase (type S1)

1987 ◽  
Vol 243 (1) ◽  
pp. 309-312 ◽  
Author(s):  
H K Young ◽  
R A Skurray ◽  
S G B Amyes
Keyword(s):  
Staphylococcus Aureus ◽  
Dihydrofolate Reductase ◽  
Specific Activity ◽  
Gram Positive ◽  
Heat Stable ◽  
Dihydrofolate Reductases ◽  
High Degree ◽  
Moderately Resistant ◽  
Identification And Characterization

The trimethoprim-resistance gene located on plasmid pSK1, originally identified in a multi-resistant Staphylococcus aureus from Australia, encodes the production of a dihydrofolate reductase (type S1), which confers a high degree of resistance to its host and is quite unlike any plasmid-encoded dihydrofolate reductase hitherto described. It has a low Mr (19,700) and has a higher specific activity than the constitutive Gram-negative plasmid dihydrofolate reductases. The type S1 enzyme is heat-stable and has a relatively low affinity for the substrate, dihydrofolate (Km 10.8 microM). It is moderately resistant to trimethoprim, and is competitively inhibited by this drug with an inhibitor-binding constant of 11.6 microM. This is the first identification and characterization of a plasmid-encoded trimethoprim-resistant dihydrofolate reductase derived from a Gram-positive species.

scholarly journals Identification of a Novel Trimethoprim Resistance Gene, dfrK, in a Methicillin-Resistant Staphylococcus aureus ST398 Strain and Its Physical Linkage to the Tetracycline Resistance Gene tet(L)

2008 ◽  
Vol 53 (2) ◽  
pp. 776-778 ◽  
Author(s):  
Kristina Kadlec ◽  
Stefan Schwarz
Keyword(s):  
Staphylococcus Aureus ◽  
Resistance Gene ◽  
Dihydrofolate Reductase ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Tetracycline Resistance ◽  
Sequence Type ◽  
Tetracycline Resistance Gene ◽  
Close Proximity ◽  
Physical Linkage ◽  
Dihydrofolate Reductases

ABSTRACT A novel trimethoprim resistance gene, designated dfrK, was detected in close proximity to the tetracycline resistance gene tet(L) on the ca. 40-kb plasmid pKKS2187 in a porcine methicillin (meticillin)-resistant Staphylococcus aureus isolate of sequence type 398. The dfrK gene encodes a 163-amino-acid dihydrofolate reductase that differs from all so-far-known dihydrofolate reductases.

scholarly journals Crystal Structure of the Dog Allergen Can f 6

2019 ◽  
Author(s):  
Gina M Clayton ◽  
Janice White ◽  
John W Kappler ◽  
Sanny K Chan
Keyword(s):  
Ligand Binding ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Cross Reactivity ◽  
Binding Partner ◽  
Sequence Identity ◽  
Natural Ligand ◽  
Binding Cavity ◽  
Can F 1 ◽  
High Degree

AbstractLipocalins represent the most important protein family of the mammalian respiratory allergens. Four of the seven named dog allergens are lipocalins: Can f 1, Can f 2, Can f 4, and Can f 6. We present the structure of Can f 6 along with data on the biophysical and biological activity of this protein in comparison with other animal lipocalins. The Can f 6 structure displays the classic lipocalin calyx-shaped ligand binding cavity within a central β-barrel similar to other lipocalins. Despite low sequence identity between the different dog lipocalin proteins, there is a high degree of structural similarity. On the other hand, Can f 6 has a similar primary sequence to cat, horse, mouse lipocalins as well as a structure that may underlie their cross reactivity. Interestingly, the entrance to the ligand binding pocket is capped by a His instead of the usually seen Tyr that may help select its natural ligand binding partner. Our highly pure recombinant Can f 6 is able to bind to human IgE (hIgE) demonstrating biological antigenicity.

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