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Substrate pathways in the nitrogenase MoFe protein by experimental identification of small molecule binding sites.

ABSTRACT: In the nitrogenase molybdenum-iron (MoFe) protein, we have identified five potential substrate access pathways from the protein surface to the FeMo-cofactor (the active site) or the P-cluster using experimental structures of Xe pressurized into MoFe protein crystals from Azotobacter vinelandii and Clostridium pasteurianum. Additionally, all published structures of the MoFe protein, including those from Klebsiella pneumoniae, were analyzed for the presence of nonwater, small molecules bound to the protein interior. Each pathway is based on identification of plausible routes from buried small molecule binding sites to both the protein surface and a metallocluster. Of these five pathways, two have been previously suggested as substrate access pathways. While the small molecule binding sites are not conserved among the three species of MoFe protein, residues lining the pathways are generally conserved, indicating that the proposed pathways may be accessible in all three species. These observations imply that there is unlikely a unique pathway utilized for substrate access from the protein surface to the active site; however, there may be preferred pathways such as those described here.

SUBMITTER: Morrison CN

PROVIDER: S-EPMC4590346 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Substrate pathways in the nitrogenase MoFe protein by experimental identification of small molecule binding sites.

Morrison Christine N CN Hoy Julie A JA Zhang Limei L Einsle Oliver O Rees Douglas C DC

Biochemistry 20150309 11

In the nitrogenase molybdenum-iron (MoFe) protein, we have identified five potential substrate access pathways from the protein surface to the FeMo-cofactor (the active site) or the P-cluster using experimental structures of Xe pressurized into MoFe protein crystals from Azotobacter vinelandii and Clostridium pasteurianum. Additionally, all published structures of the MoFe protein, including those from Klebsiella pneumoniae, were analyzed for the presence of nonwater, small molecules bound to th ...[more]

PMID: 25710326

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Project description:Background Analysis of the 3D structures of protein–ligand binding sites can provide valuable insights for drug discovery. Binding site comparison (BSC) studies can be employed to elucidate the function of orphan proteins or to predict the potential for polypharmacology. Many previous binding site analyses only consider binding sites surrounding an experimentally observed bound ligand. Results To encompass potential protein–ligand binding sites that do not have ligands known to bind, we have incorporated fpocket cavity detection software and assessed the impact of this inclusion on BSC performance. Using fpocket, we generated a database of ligand-independent potential binding sites and applied the BSC tool, SiteHopper, to analyze similarity relationships between protein binding sites. We developed a method for clustering potential binding sites using a curated dataset of structures for six therapeutically relevant proteins from diverse protein classes in the protein data bank. Two clustering methods were explored; hierarchical clustering and a density-based method adept at excluding noise and outliers from a dataset. We introduce circular plots to visualize binding site structure space. From the datasets analyzed in this study, we highlight a structural relationship between binding sites of cationic trypsin and prothrombin, protein targets known to bind structurally similar small molecules, exemplifying the potential utility of objectively and holistically mapping binding site space from the structural proteome. Conclusions We present a workflow for the objective mapping of potential protein–ligand binding sites derived from the currently available structural proteome. We show that ligand-independent binding site detection tools can be introduced without excessive penalty on BSC performance. Clustering combined with intuitive visualization tools can be applied to map relationships between the 3D structures of protein binding sites.Graphical abstract Mapping binding site space. Electronic supplementary material The online version of this article (doi:10.1186/s13321-016-0180-0) contains supplementary material, which is available to authorized users.

Dataset Information

Substrate pathways in the nitrogenase MoFe protein by experimental identification of small molecule binding sites.

Publications

Substrate pathways in the nitrogenase MoFe protein by experimental identification of small molecule binding sites.

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