Computer modeling of human angiogenin-dinucleotide substrate interaction

Madhusudhan, M.S.; Vishveshwara, Saraswathi

doi:10.1002/1097-0134(20010101)42:1<125::aid-prot120>3.0.co;2-k

Cited by 5 publications

(16 citation statements)

References 39 publications

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“…The starting structure for the native bovine angiogenin was a crystal structure9 (PDB code 1AGI), and the starting template for docking the dinucleotide substrate was that of the modeled bovine angiogenin‐mononucleotide complex 5. The second nucleotide was built onto the template of the existing first by using a grid search method similar to that described in the previous study 7. Steric‐free models possessing the important protein–ligand interactions were chosen for all three ligand‐bound complexes of bovine angiogenin.…”

Section: Methodsmentioning

confidence: 99%

“…The cleavage of RNA is a function they share in common, and this is crucial for their biological activity 1. To understand the similarities and diversities in their functions, we have been investigating the nature of ligand binding in these proteins2–7 for ribonuclease activity at a molecular level. Angiogenin is an interesting member of the RNase A family.…”

Section: Introductionmentioning

confidence: 99%

“…Subtle differences in the sequence and architecture tell them apart. In our previous study,7 we focused on the dinucleotide substrate binding to human angiogenin. Here we discuss our efforts on bovine angiogenin and compare the nature of binding in the two systems.…”

Section: Introductionmentioning

confidence: 99%

“…The sequence is R67, G68, and D69 in bovine and R66, E67, and N68 in human angiogenin. In the human case, our recent studies on docking of substrates7 have shown that this region interacts with the second base of the substrate.…”

Section: Introductionmentioning

confidence: 99%

“…From an analysis of the docked structures and the MD simulation trajectories we investigate details of protein–substrate interactions and examine the basis for bovine angiogenin's substrate specificity. The results are also compared with the docked structures of substrates with human angiogenin 7. A general, consensus topology of dinucleotide binding to RNase A family of proteins has been obtained from the simulations and annealed structures.…”

Section: Introductionmentioning

confidence: 99%

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Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

2001

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We have undertaken the modeling of substrate-bound structures of angiogenin. In our recent study, we modeled the dinucleotide ligand binding to human angiogenin. In the present study, the substrates CpG, UpG, and CpA were docked onto bovine angiogenin. This was achieved by overcoming the problem of an obstruction to the B1 site by the C-terminus and identifying residues that bind to the second base. The modeled complexes retain biochemically important interactions. The docked models were subjected to 1 ns of molecular dynamics, and structures from the simulation were refined by using simulated annealing. Our models explained the enzyme's specificity for both B1 and B2 bases as observed experimentally. The nature of binding of the dinucleotide substrate was compared with that of the mononucleotide product. The models of these complexes were also compared with those obtained earlier with human angiogenin. On the basis of the simulations and annealed structures, we came up with a consensus topology of dinucleotide ligands that binds to human and bovine angiogenins. This dinucleotide conformation can serve as a starting model for ligand-bound complex structures for RNase A family of proteins. We demonstrated this capability by generating the complex structure of CpA bound to eosinophilderived neurotoxin (EDN) by fitting the consensus topology of CpA to the crystal structure of native EDN. Proteins 2001;45:30 -39.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

2001

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Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin

Merlino

Vitagliano

Ceruso³

et al. 2003

Proteins

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The analysis of the dynamic behavior of enzymes is fundamental to structural biology. A direct relationship between protein flexibility and biological function has been shown for bovine pancreatic ribonuclease (RNase A) (Rasmussen et al., Nature 1992;357:423-424). More recently, crystallographic studies have shown that functional motions in RNase A involve the enzyme beta-sheet regions that move concertedly on substrate binding and release (Vitagliano et al., Proteins 2002;46:97-104). These motions have been shown to correspond to intrinsic dynamic properties of the native enzyme by molecular dynamics (MD) simulations. To unveil the occurrence of these collective motions in other members of pancreatic-like superfamily, we carried out MD simulations on human angiogenin (Ang). Essential dynamics (ED) analyses performed on the trajectories reveal that Ang exhibits collective motions similar to RNase A, despite the limited sequence identity (33%) of the two proteins. Furthermore, we show that these collective motions are also present in ensembles of experimentally determined structures of both Ang and RNase A. Finally, these subtle concerted beta-sheet motions were also observed for other two members of the pancreatic-like superfamily by comparing the ligand-bound and ligand-free structures of these enzymes. Taken together, these findings suggest that pancreatic-like ribonucleases share an evolutionary conserved dynamic behavior consisting of subtle beta-sheet motions, which are essential for substrate binding and release.

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Dynamics of the Native and the Ligand-bound Structures of Eosinophil Cationic Protein: Network of Hydrogen Bonds at the Catalytic Site

Sanjeev

Vishveshwara

2005

Journal of Biomolecular Structure and Dynamics

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Eosinophil Cationic Protein (ECP) is sequentially and structurally similar to ribonuclease A (RNase A). It belongs to the RNase A family of proteins and the RNA catalysis is essential to its biological function. In the present study, we have generated the dinucleotide-bound structures of ECP by docking the dinucleotides to a number of molecular dynamics (MD) generated ECP structures. The stability of the docked enzyme-ligand complexes was ascertained by extensive MD simulations. The modes of ligand binding are explored by essential dynamics studies. The role of water molecules in the stability of the complex and in the catalysis was investigated. The active site residues form a complex network of connections with the ligand and with a water molecule. The catalytic mechanism of the RNA cleavage is examined on the basis of the active site geometry obtained by the simulations.

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Computer modeling of human angiogenin-dinucleotide substrate interaction

Cited by 5 publications

References 39 publications

Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin

Dynamics of the Native and the Ligand-bound Structures of Eosinophil Cationic Protein: Network of Hydrogen Bonds at the Catalytic Site

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