Identification of Tertiary Structure Resemblance in Proteins Using a Maximal Common Subgraph Isomorphism Algorithm

Grindley, Helen M.; Artymiuk, Peter J.; Rice, David W.; Willett, Peter

doi:10.1006/jmbi.1993.1074

Cited by 244 publications

(152 citation statements)

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“…This is confirmed by the PROTEP (Grindley et al, 1993) and DALI (Holm and Sander, 1993) searches, which find a notable structural resemblance only in TSs. Although T4 CH and TS subunits share a common fold, there exist many significant structural differences (Figure 4).…”

Section: Similarity To Thymidylate Synthasessupporting

confidence: 58%

Crystal structure of deoxycytidylate hydroxymethylase from bacteriophage T4, a component of the deoxyribonucleoside triphosphate-synthesizing complex

1999

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Bacteriophage T4 deoxycytidylate hydroxymethylase (EC 2.1.2.8), a homodimer of 246-residue subunits, catalyzes hydroxymethylation of the cytosine base in deoxycytidylate (dCMP) to produce 5-hydroxymethyldCMP. It forms part of a phage DNA protection system and appears to function in vivo as a component of a multienzyme complex called deoxyribonucleoside triphosphate (dNTP) synthetase. We have determined its crystal structure in the presence of the substrate dCMP at 1.6 Å resolution. The structure reveals a subunit fold and a dimerization pattern in common with thymidylate synthases, despite low (~20%) sequence identity. Among the residues that form the dCMP binding site, those interacting with the sugar and phosphate are arranged in a configuration similar to the deoxyuridylate binding site of thymidylate synthases. However, the residues interacting directly or indirectly with the cytosine base show a more divergent structure and the presumed folate cofactor binding site is more open. Our structure reveals a water molecule properly positioned near C-6 of cytosine to add to the C-7 methylene intermediate during the last step of hydroxymethylation. On the basis of sequence comparison and crystal packing analysis, a hypothetical model for the interaction between T4 deoxycytidylate hydroxymethylase and T4 thymidylate synthase in the dNTP-synthesizing complex has been built. Keywords: bacteriophage T4/deoxycytidylate hydroxymethylase/deoxyuridylate hydroxymethylase/ dNTP-synthesizing complex/thymidylate synthase

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Section: Similarity To Thymidylate Synthasessupporting

confidence: 58%

Crystal structure of deoxycytidylate hydroxymethylase from bacteriophage T4, a component of the deoxyribonucleoside triphosphate-synthesizing complex

1999

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“…Maximal clique enumeration (MCE) is ubiquitous in real world problems. Examples of the uses of MCE include identification of common secondary structure elements of proteins [7], detection of protein-protein interaction complexes [19], clustering of similar mass spectrometry spectra [17], and detection of social heirarchy from email communications [15]. Thus, efficient MCE algorithms are of high value.…”

Section: Algorithm Overviewmentioning

confidence: 99%

Lessons Learned from Exploring the Backtracking Paradigm on the GPU

Jenkins

Arkatkar

Owens

et al. 2011

Euro-Par 2011 Parallel Processing

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Abstract. We explore the backtracking paradigm with properties seen as sub-optimal for GPU architectures, using as a case study the maximal clique enumeration problem, and find that the presence of these properties limit GPU performance to approximately 1.4-2.25 times a single CPU core. The GPU performance "lessons" we find critical to providing this performance include a coarse-and-fine-grain parallelization of the search space, a low-overhead load-balanced distribution of work, global memory latency hiding through coalescence, saturation, and shared memory utilization, and the use of GPU output buffering as a solution to irregular workloads and a large solution domain. We also find a strong reliance on an efficient global problem structure representation that bounds any efficiencies gained from these lessons, and discuss the meanings of these results to backtracking problems in general.

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“…Because the best geometric match corresponds to a linear alignment, these matches may imply evolutionary divergence between members of the family. Alexandrov et al, 1992;Grindley et al, 1993). In all of them, either the sequential order of the matches must be conserved, or the matching is carried out between fragments of contiguous residues in the chains.…”

Section: Scanning the Databasementioning

confidence: 99%

Three‐dimensional, sequence order‐independent structural comparison of a serine protease against the crystallographic database reveals active site similarities: Potential implications to evolution and to protein folding

et al. 1994

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We have recently developed a fast approach to comparisons of 3-dimensional structures. Our method is unique, treating protein structures as collections of unconnected points (atoms) in space. It is completely independent of the amino acid sequence order. It is unconstrained by insertions, deletions, and chain directionality. It matches single, isolated amino acids between 2 different structures strictly by their spatial positioning regardless of their relative sequential position in the amino acid chain. It automatically detects a recurring 3D motif in protein molecules. No predefinition of the motif is required. The motif can be either in the interior of the proteins or on their surfaces. In this work, we describe an enhancement over our previously developed technique, which considerably reduces the complexity of the algorithm. This results in an extremely fast technique. A typical pairwise comparison of 2 protein molecules requires less than 3 s on a workstation. We have scanned the structural database with dozens of probes, successfully detecting structures that are similar to the probe. To illustrate the power of this method, we compare the structure of a trypsin-like serine protease against the structural database. Besides detecting homologous trypsin-like proteases, we automatically obtain 3D, sequence order-independent, active-site similarities with subtilisin-like and sulfhydryl proteases. These similarities equivalence isolated residues, not conserving the linear order of the amino acids in the chains. The active-site similarities are well known and have been detected by manually inspecting the structures in a time-consuming, laborious procedure. This is the first time such equivalences are obtained automatically from the comparison of full structures. The far-reaching advantages and the implications of our novel algorithm to studies of protein folding, to evolution, and to searches for pharmacophoric patterns are discussed.Keywords: computer vision; protease active sites; protein database structural comparison; protein folding; 3D protein motifsWe have recently developed an extremely fast, template-free, sequence order-independent technique for the comparisons of the 3-dimensional structures of proteins. There are 3 novel aspects in our method. First, we compare the 3D structures of proteins (or any biological macromolecule) completely regardless of the order of the residues in the chain. This allows us to detect similarities between protein molecules, whether these are on their surfaces or in their interior. Our computer vision-based algorithm views atoms as collections of unconnected points in space.Reprint requests to: Ruth Nussinov, Building 469, Room 151, NCI-FCRF, Frederick, Maryland 21702; e-mail: ruthn@fcrfvl.ncifcrf.gov. This truly 3D approach overcomes a major limitation inherent in other structural comparison techniques which require that the linear order of the amino acid sequences be conserved (e.g., Matthews & Rossmann, 1985). Although some techniques overcome the insertion/del...

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Identification of Tertiary Structure Resemblance in Proteins Using a Maximal Common Subgraph Isomorphism Algorithm

Cited by 244 publications

References 0 publications

Crystal structure of deoxycytidylate hydroxymethylase from bacteriophage T4, a component of the deoxyribonucleoside triphosphate-synthesizing complex

Crystal structure of deoxycytidylate hydroxymethylase from bacteriophage T4, a component of the deoxyribonucleoside triphosphate-synthesizing complex

Lessons Learned from Exploring the Backtracking Paradigm on the GPU

Three‐dimensional, sequence order‐independent structural comparison of a serine protease against the crystallographic database reveals active site similarities: Potential implications to evolution and to protein folding

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