Modeling of metal interaction geometries for protein–ligand docking

Seebeck, Birte; Reulecke, Ingo; Kämper, Andreas; Rarey, Matthias

doi:10.1002/prot.21818

Cited by 59 publications

(62 citation statements)

References 62 publications

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“…Manganese is a trace element in eukaryotes but appears to be present in higher concentrations in cyanobacteria (32) and could be a physiological cofactor for Cya2. The increased activity of eukaryotic cyclases in presence of Mn 2ϩ could be an evolutionary remnant or simply be due to the larger size and more flexible coordination geometry of manganese (9,33).…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of the guanylyl cyclase Cya2

Rauch

Leipelt²,

Russwurm³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

139

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Cyclic GMP (cGMP) is an important second messenger in eukaryotes. It is formed by guanylyl cyclases (GCs), members of the nucleotidyl cyclases class III, which also comprises adenylyl cyclases (ACs) from most organisms. To date, no structures of eukaryotic GCs are available, and all bacterial class III proteins were found to be ACs. Here we describe the biochemical and structural characterization of the class III cyclase Cya2 from cyanobacterium Synechocystis PCC6803. Cya2 shows high specificity for GTP versus ATP, revealing it to be the first bacterial GC, and sequence similarity searches indicate that GCs are also present in other bacteria. The crystal structure of Cya2 provides first structural insights into the universal GC family. Structure and mutagenesis studies show that a conserved glutamate, assisted by an interacting lysine, dominates substrate selection by forming hydrogen bonds to the substrate base. We find, however, that a second residue involved in substrate selection has an unexpected sterical role in GCs, different from its hydrogen bonding function in the related ACs. The structure identifies a tyrosine that lines the guanine binding pocket as additional residue contributing to substrate specificity. Furthermore, we find that substrate specificity stems from faster turnover of GTP, rather than different affinities for GTP and ATP, implying that the specificity-determining interactions are established after the binding step.bacterial ͉ cGMP T he second messenger cGMP plays a central role in regulating bodily function such as the cardiovascular system and vision (1). In mammals, cGMP is formed by a family of guanylyl cyclases comprising a soluble GC (sGC) and several transmembrane receptor enzymes (rGCs). Mammalian GCs have a catalytic domain fused, via a central domain, to either an extracellular ligand binding domain (rGCs) or a nitric oxide binding heme domain (sGC) (1-3). In lower eukaryotes, guanylyl cyclase domains are fused to a variety of regulatory domains and function in processes such as cell motility control or chemotaxis (4).All known guanylyl cyclases belong to class III of the purine nucleotidyl cyclase family, which was subdivided in six phylogenetically separated classes, I-VI, based on sequence homologies within the catalytic cores (5, 6). Class III also comprises adenylyl cyclases (ACs) from almost all domains of life (no member has been confirmed in plants), including most bacteria (7). GCs, in contrast, have been described only in Dictyostelium and higher organisms, and their existence in prokaryotes has only been speculated upon (8). Despite their physiological importance, no structural data on GC enzymes are available to date. For class III ACs, in contrast, several crystal structures have been reported, revealing a conserved basic architecture of the catalytic cores (6, 9-11), which is assumed to be shared by GCs (1, 12).Class III cyclases require dimerization of two catalytic domains for activity, which leads to formation of shared active sites in ACs (6, 7). Modeling st...

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Section: Discussionmentioning

confidence: 99%

Crystal structure of the guanylyl cyclase Cya2

Rauch

Leipelt²,

Russwurm³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

139

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“…The fact that all the mutant receptors possessed in vitro guanylyl cyclase activity when measured using MnGTP as a substrate showed that the cyclase domains were able to dimerize in a functional manner when Mn 2ϩ was present as the metal co-factor. Perhaps the larger size and flexible co-ordination geometry of Mn 2ϩ (42) allows it to bind and form a functional catalytic site even in the presence of mutations that render the guanylyl cyclase domain poorly active when measured with MgGTP as a substrate. Nevertheless, because some linker mutant receptors showed robust guanylyl cyclase activity even when MgGTP alone was used as a substrate, we suggest that the linker region has an inhibitory role on the receptor guanylyl cyclase domain, perhaps by preventing the two catalytic domain subunits from juxtaposing themselves in a way suitable for catalysis in the absence of the ligand.…”

Section: Discussionmentioning

confidence: 99%

The Linker Region in Receptor Guanylyl Cyclases Is a Key Regulatory Module

Saha

Biswas

Kondapalli

et al. 2009

Journal of Biological Chemistry

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Receptor guanylyl cyclases are multidomain proteins, and ligand binding to the extracellular domain increases the levels of intracellular cGMP. The intracellular domain of these receptors is composed of a kinase homology domain (KHD), a linker of ϳ70 amino acids, followed by the C-terminal guanylyl cyclase domain. Mechanisms by which these receptors are allosterically regulated by ligand binding to the extracellular domain and ATP binding to the KHD are not completely understood. Here we examine the role of the linker region in receptor guanylyl cyclases by a series of point mutations in receptor guanylyl cyclase C. The linker region is predicted to adopt a coiled coil structure and aid in dimerization, but we find that the effects of mutations neither follow a pattern predicted for a coiled coil peptide nor abrogate dimerization. Importantly, this region is critical for repressing the guanylyl cyclase activity of the receptor in the absence of ligand and permitting ligand-mediated activation of the cyclase domain. Mutant receptors with high basal guanylyl cyclase activity show no further activation in the presence of non-ionic detergents, suggesting that hydrophobic interactions in the basal and inactive conformation of the guanylyl cyclase domain are disrupted by mutation. Equivalent mutations in the linker region of guanylyl cyclase A also elevated the basal activity and abolished ligand-and detergent-mediated activation. We, therefore, have defined a key regulatory role for the linker region of receptor guanylyl cyclases which serves as a transducer of information from the extracellular domain via the KHD to the catalytic domain.In transmembrane receptors a series of conformational changes are required to transmit the information of ligand binding (an extracellular signal) to the interior of the cell, resulting in either altered interaction with signaling intermediates or in the regulation of a catalytic activity present in the receptor. In these multidomain receptors, where the ligand binding and effector domains are present in the same polypeptide chain, the relay of conformational changes is under the exquisite control of post-translational modifications or precise structural alterations.Receptor guanylyl cyclases (GCs) 4 have an N-terminal extracellular ligand binding domain, a single transmembrane domain, and a C-terminal intracellular domain (1). Binding of ligands to the extracellular domain elicits a conformational change that increases the guanylyl cyclase activity of the receptor, resulting in increased cGMP production. The intracellular domain of receptor GCs contains a region that shares considerable sequence similarity to protein kinases and is referred to as the kinase homology domain (KHD). Binding of ATP to the KHD induces a conformational change that regulates cGMP production by the guanylyl cyclase domain (2). Thus, receptor GCs exemplify the intricate interactions between domains in transducing the signal from an extracellular ligand to the interior of the cell.The amino acid sequences of ...

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“…Modeling of complex bonds still represents a challenge in the development of docking tools, especially due to parameterization and accurate modeling of interaction geometry (a geometry of complex bond is very hard to reproduce) [49,50].…”

Section: Modeling Of Complex Bonds By Selected Docking Toolsmentioning

confidence: 99%

“…The rest of selected docking programs unfortunately have limitations in regard to complex bonds modeling [49].…”

Section: Modeling Of Complex Bonds By Selected Docking Toolsmentioning

confidence: 99%

Comparative evaluation of several docking tools for docking small molecule ligands to DC-SIGN

2015

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Five docking tools, namely AutoDock, FRED, CDOCKER, FlexX and GOLD, have been critically examined, with the aim of selecting those most appropriate for use as docking tools for docking molecules to the lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). This lectin has been selected for its rather non-druggable binding site, which enables complex interactions that guide the binding of the core monosaccharide. Since optimal orientation is crucial for forming coordination bonds, it was important to assess whether the selected docking tools could reproduce the optimal binding conformation for several oligosaccharides that are known to bind DC-SIGN. Our results show that even widely used docking programs have certain limitations when faced with a rather shallow and featureless binding site, as is the case of DC-SIGN. The FRED docking software (OpenEye Scientific Software, Inc.) was found to score as the best tool for docking ligands to DC-SIGN. The performance of FRED was further assessed on another lectin, Langerin. We have demonstrated that this validated docking protocol could be used for docking to other lectins similar to DC-SIGN.

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Modeling of metal interaction geometries for protein–ligand docking

Cited by 59 publications

References 62 publications

Crystal structure of the guanylyl cyclase Cya2

Crystal structure of the guanylyl cyclase Cya2

The Linker Region in Receptor Guanylyl Cyclases Is a Key Regulatory Module

Comparative evaluation of several docking tools for docking small molecule ligands to DC-SIGN

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