scholarly journals PREMONITION - Preprocessing motifs in protein structures for search acceleration

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 217 ◽  
Author(s):  
Sandeep Chakraborty ◽  
Basuthkar J. Rao ◽  
Bjarni Asgeirsson ◽  
Ravindra Venkatramani ◽  
Abhaya M. Dandekar
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Active Site ◽  
Active Sites ◽  
Protein Structures ◽  
3D Structure ◽  
Search Space ◽  
Computational Method ◽  
Computational Time ◽  
Active Site Residues

The remarkable diversity in biological systems is rooted in the ability of the twenty naturally occurring amino acids to perform multifarious catalytic functions by creating unique structural scaffolds known as the active site. Finding such structrual motifs within the protein structure is a key aspect of many computational methods. The algorithm for obtaining combinations of motifs of a certain length, although polynomial in complexity, runs in non-trivial computer time. Also, the search space expands considerably if stereochemically equivalent residues are allowed to replace an amino acid in the motif. In the present work, we propose a method to precompile all possible motifs comprising of a set (n=4 in this case) of predefined amino acid residues from a protein structure that occur within a specified distance (R) of each other (PREMONITION). PREMONITION rolls a sphere of radius R along the protein fold centered at the C atom of each residue, and all possible motifs are extracted within this sphere. The number of residues that can occur within a sphere centered around a residue is bounded by physical constraints, thus setting an upper limit on the processing times. After such a pre-compilation step, the computational time required for querying a protein structure with multiple motifs is considerably reduced. Previously, we had proposed a computational method to estimate the promiscuity of proteins with known active site residues and 3D structure using a database of known active sites in proteins (CSA) by querying each protein with the active site motif of every other residue. The runtimes for such a comparison is reduced from days to hours using the PREMONITION methodology.

scholarly journals The Uncommon Active Site of D-Amino Acid Transaminase from Haliscomenobacter hydrossis: Biochemical and Structural Insights into the New Enzyme

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 5053
Author(s):  
Alina K. Bakunova ◽  
Alena Yu. Nikolaeva ◽  
Tatiana V. Rakitina ◽  
Tatiana Y. Isaikina ◽  
Maria G. Khrenova ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Structural Analysis ◽  
Active Site ◽  
Active Sites ◽  
Structural Basis ◽  
Active Site Residues ◽  
Type Iv ◽  
Fold Type ◽  
Arginine Residues

Among industrially important pyridoxal-5’-phosphate (PLP)-dependent transaminases of fold type IV D-amino acid transaminases are the least studied. However, the development of cascade enzymatic processes, including the synthesis of D-amino acids, renewed interest in their study. Here, we describe the identification, biochemical and structural characterization of a new D-amino acid transaminase from Haliscomenobacter hydrossis (Halhy). The new enzyme is strictly specific towards D-amino acids and their keto analogs; it demonstrates one of the highest rates of transamination between D-glutamate and pyruvate. We obtained the crystal structure of the Halhy in the holo form with the protonated Schiff base formed by the K143 and the PLP. Structural analysis revealed a novel set of the active site residues that differ from the key residues forming the active sites of the previously studied D-amino acids transaminases. The active site of Halhy includes three arginine residues, one of which is unique among studied transaminases. We identified critical residues for the Halhy catalytic activity and suggested functions of the arginine residues based on the comparative structural analysis, mutagenesis, and molecular modeling simulations. We suggested a strong positive charge in the O-pocket and the unshaped P-pocket as a structural code for the D-amino acid specificity among transaminases of PLP fold type IV. Characteristics of Halhy complement our knowledge of the structural basis of substrate specificity of D-amino acid transaminases and the sequence-structure-function relationships in these enzymes.

scholarly journals Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

2018 ◽  
Vol 475 (1) ◽  
pp. 273-288 ◽  
Author(s):  
Thomas M. Harper ◽  
Cynthia M. June ◽  
Magdalena A. Taracila ◽  
Robert A. Bonomo ◽  
Rachel A. Powers ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acinetobacter Baumannii ◽  
Active Site ◽  
Active Sites ◽  
Protein Structures ◽  
Amino Acid Substitutions ◽  
The Third ◽  
Class D ◽  
Late Generation ◽  
Loop Flexibility

OXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced ∼3-fold and 20-fold, respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical with that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of β-lactam drugs.

scholarly journals DeepCDpred: Inter-residue Distance and Contact Prediction for Improved Prediction of Protein Structure

2018 ◽  
Author(s):  
Shuangxi Ji ◽  
Tŭgçe Oruç ◽  
Liam Mead ◽  
Muhammad Fayyaz Rehman ◽  
Christopher M Thomas ◽  
...  
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Assessment Tool ◽  
Protein Structures ◽  
3D Structure ◽  
Disease Diagnosis ◽  
Accurate Prediction ◽  
Prediction Methods ◽  
Model Assessment ◽  
Contact Prediction

AbstractRapid, accurate prediction of protein structure from amino acid sequence would accelerate fields as diverse as drug discovery, synthetic biology and disease diagnosis. Massively improved prediction of protein structures has been driven by improving the prediction of the amino acid residues that contact in their 3D structure. For an average globular protein, around 92% of all residue pairs are non-contacting, therefore accurate prediction of only a small percentage of inter-amino acid distances could increase the number of constraints to guide structure determination. We have trained deep neural networks to predict inter-residue contacts and distances. Distances are predicted with an accuracy better than most contact prediction techniques. Addition of distance constraints improved de novo structure predictions for test sets of 158 protein structures, as compared to using the best contact prediction methods alone. Importantly, usage of distance predictions allows the selection of better models from the structure pool without a need for an external model assessment tool. The results also indicate how the accuracy of distance prediction methods might be improved further.

scholarly journals Derived amino acid sequence and identification of active site residues of Escherichia coli beta-hydroxydecanoyl thioester dehydrase.

1988 ◽  
Vol 263 (10) ◽  
pp. 4641-4646 ◽  
Author(s):  
J E Cronan ◽  
W B Li ◽  
R Coleman ◽  
M Narasimhan ◽  
D de Mendoza ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Amino Acid Sequence ◽  
Active Site ◽  
Active Site Residues

scholarly journals Structural Modeling and Analysis of Pregnancy-Associated Glycoprotein-1 of Buffalo (Bubalus bubalis)

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Jerome Andonissamy ◽  
S. K. Singh ◽  
S. K. Agarwal
Keyword(s):  
Protein Structure ◽  
Active Sites ◽  
Structural Model ◽  
Protein Structures ◽  
Structural Modeling ◽  
Bubalus Bubalis ◽  
High Energy ◽  
Docking Studies ◽  
Modeling And Analysis ◽  
Structural Conformity

The present study was conducted to design and analyze the structural model of buffalo pregnancy-associated glycoprotein-1 (PAG-1) using bioinformatics. Structural modeling of the deduced buffalo PAG-1 protein was done using PHYRE, CONSURF servers and its structure was subsequently constructed using MODELLER 9.9 and PyMOL softwares Buffalo PAG-1 structural conformity was analyzed using PROSA, WHATIF, and 3D-PSSM servers. Designed buffalo PAG-1 protein structure on BLAST analysis retrieved protein structures belonging to aspartic proteinase family. Moreover in silico analysis revealed buffalo PAG-1 protein retained bilobed structure with pepstatin-binding clefts near the active sites by docking studies with pepstatin A using PatchDock server. Structural studies revealed that the amino and carboxy terminal containing aspartic residues are highly conserved and buried within the protein structure. Structural conformity studies showed that more than 90% of the residues lie inside favored and allowed regions. It was also deduced that buffalo PAG-1 possesses low and high energy zones with a very low threshold for proteolysis ascertaining the stableness of the buffalo PAG-1 protein structure. This study depicts the structural conformity and stability of buffalo PAG-1 protein.

scholarly journals Novel 4,6-Disubstituted s-Triazin-2-yl Amino Acid Derivatives as Promising Antifungal Agents

2020 ◽  
Vol 6 (4) ◽  
pp. 237
Author(s):  
Rakia Abd Alhameed ◽  
Zainab Almarhoon ◽  
Essam N. Sholkamy ◽  
Salman Ali Khan ◽  
Zaheer Ul-Haq ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antifungal Activity ◽  
Active Site ◽  
Antifungal Agents ◽  
Docking Studies ◽  
Amino Acid Derivatives ◽  
Active Site Residues ◽  
Standard Drug ◽  
Drug Compounds ◽  
Inhibition Zones

A novel series of 4,6-disubstituted s-triazin-2-yl amino acid derivatives was prepared and characterized. Most of them showed antifungal activity against Candida albicans compared to clotrimazole (standard drug). Compounds bearing aniline derivatives, piperidine and glycine on the triazine core showed the highest inhibition zones at concentrations of 50, 100, 200, and 300 μg per disc. In addition, docking studies revealed that all the compounds accommodated well in the active site residues of N-myristoltransferase (NMT) and exhibited complementarity, which explains the observed antifungal activity. Interestingly, none of these compounds showed antibacterial activity.

scholarly journals The Convergence of the Hedgehog/Intein Fold in Different Protein Splicing Mechanisms

2020 ◽  
Vol 21 (21) ◽  
pp. 8367
Author(s):  
Hannes M. Beyer ◽  
Salla I. Virtanen ◽  
A. Sesilja Aranko ◽  
Kornelia M. Mikula ◽  
George T. Lountos ◽  
...  
Keyword(s):  
Amino Acid ◽  
Active Sites ◽  
Bond Cleavage ◽  
Structural Basis ◽  
Protein Splicing ◽  
Active Site Residues ◽  
Class 1 ◽  
Characteristic Sequences ◽  
Dynamics Simulations ◽  
Esterification Reactions

Protein splicing catalyzed by inteins utilizes many different combinations of amino-acid types at active sites. Inteins have been classified into three classes based on their characteristic sequences. We investigated the structural basis of the protein splicing mechanism of class 3 inteins by determining crystal structures of variants of a class 3 intein from Mycobacterium chimaera and molecular dynamics simulations, which suggested that the class 3 intein utilizes a different splicing mechanism from that of class 1 and 2 inteins. The class 3 intein uses a bond cleavage strategy reminiscent of proteases but share the same Hedgehog/INTein (HINT) fold of other intein classes. Engineering of class 3 inteins from a class 1 intein indicated that a class 3 intein would unlikely evolve directly from a class 1 or 2 intein. The HINT fold appears as structural and functional solution for trans-peptidyl and trans-esterification reactions commonly exploited by diverse mechanisms using different combinations of amino-acid types for the active-site residues.

Temperature and Proteins: Little Things Can Mean a Lot

Physiology ◽  
1996 ◽  
Vol 11 (2) ◽  
pp. 72-77 ◽  
Author(s):  
GN Somero
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Protein Stability ◽  
Active Sites ◽  
Protein Structures ◽  
Free Energies ◽  
Adaptive Changes ◽  
Highly Sensitive

Protein structures are highly sensitive to temperature because their net free energies of stabilization are low, about equal to energies associated with formation of a few noncovalent ("weak") bonds. Temperature-adaptive changes in protein stability and fucntion may result from minor changes in amino acid sequence at regions outside active sites and from accumulation of stabilizing solutes in the cell.

scholarly journals Identification of Essential Residues in Apolipoprotein N-Acyl Transferase, a Member of the CN Hydrolase Family

2007 ◽  
Vol 189 (12) ◽  
pp. 4456-4464 ◽  
Author(s):  
Dominique Vidal-Ingigliardi ◽  
Shawn Lewenza ◽  
Nienke Buddelmeijer
Keyword(s):  
Active Site ◽  
Structural Model ◽  
Protein Structures ◽  
Catalytic Triad ◽  
Site Directed Mutagenesis ◽  
Acyl Transferase ◽  
Active Site Residues ◽  
Flexible Arms ◽  
Hydrolase Family

ABSTRACT Apolipoprotein N-acyl transferase (Lnt) is an essential membrane-bound protein involved in lipid modification of all lipoproteins in gram-negative bacteria. Essential residues in Lnt of Escherichia coli were identified by using site-directed mutagenesis and an in vivo complementation assay. Based on sequence conservation and known protein structures, we predict a model for Lnt, which is a member of the CN hydrolase family. Besides the potential catalytic triad E267-K335-C387, four residues that directly affect the modification of Braun's lipoprotein Lpp are absolutely required for Lnt function. Residues Y388 and E389 are part of the hydrophobic pocket that constitutes the active site. Residues W237 and E343 are located on two flexible arms that face away from the active site and are expected to open and close upon the binding and release of phospholipid and/or apolipoprotein. Substitutions causing temperature-dependent effects were located at different positions in the structural model. These mutants were not affected in protein stability. Lnt proteins from other proteobacteria, but not from actinomycetes, were functional in vivo, and the essential residues identified in Lnt of E. coli are conserved in these proteins.

scholarly journals 3D Structure Modeling of Alpha-Amino Acid Ester Hydrolase from Xanthomonas rubrilineans

Acta Naturae ◽  
2013 ◽  
Vol 5 (4) ◽  
pp. 62-70 ◽  
Author(s):  
S. A. Zarubina ◽  
I. V. Uporov ◽  
E. A. Fedorchuk ◽  
V. V. Fedorchuk ◽  
A. V. Sklyarenko ◽  
...  
Keyword(s):  
Amino Acid ◽  
Active Site ◽  
Acid Ester ◽  
Rational Design ◽  
3D Structure ◽  
Catalytic Triad ◽  
Amino Acid Ester ◽  
Dimensional Structure ◽  
Ester Hydrolase ◽  
Alpha Amino Acid

Alpha-amino acid ester hydrolase (EC 3.1.1.43, AEH) is a promising biocatalyst for the production of semi-synthetic -lactam antibiotics, penicillins and cephalosporins. The AEH gene from Xanthomonas rubrilineans (XrAEH) was recently cloned in this laboratory. The three-dimensional structure of XrAEH was simulated using the homology modeling method for rational design experiments. The analysis of the active site was performed, and its structure was specified. The key amino acid residues in the active site - the catalytic triad (Ser175, His341 and Asp308), oxyanion hole (Tyr83 and Tyr176), and carboxylate cluster (carboxylate groups of Asp209, Glu310 and Asp311) - were identified. It was shown that the optimal configuration of residues in the active site occurs with a negative net charge -1 in the carboxylate cluster. Docking of different substrates in the AEH active site was carried out, which allowed us to obtain structures of XrAEH complexes with the ampicillin, amoxicillin, cephalexin, D-phenylglycine, and 4-hydroxy-D-phenylglycine methyl ester. Modeling of XrAEH enzyme complexes with various substrates was used to show the structures for whose synthesis this enzyme will show the highest efficiency.

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