New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents

Brink, Alice; Helliwell, John R.

doi:10.1107/s2052252517003475

Cited by 21 publications

(15 citation statements)

References 55 publications

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“…Most parts of the protocol can also be applied to the most frequently encountered and biologically relevant alkali and alkaline earth metals (Na + , Mg 2+ , Ca 2+ , K + ). With modification and careful consideration from other works 16–20 , the protocol should also prove valuable for metals present only in the event of toxicity or when introduced as a part of a drug’s active compound (Cd 2+ , Au 1+ , Pt 2+ , Hg 2+ , Pb 2+ ).…”

Section: Introductionmentioning

confidence: 99%

“…Similar methods have been developed to identify metal binding sites and metal ligands in the reaction between proteins and metal-based drugs containing Re, Ru, Pt or Au. A similar two-wavelength procedure has been used to unambiguously identify a Re ion in the structure of the lysozyme-Re compound adduct 16 and to discriminate between Cd 2+ and Pt 2+ in the adducts formed in the reaction between cisplatin or carboplatin and ferritin 17 . Moreover, including data with a high R merge but significant CC 1/2 , can improve the electron density map to allow for the definition of metals 18,19 .…”

Section: Introductionmentioning

confidence: 99%

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Characterizing metal-binding sites in proteins with X-ray crystallography

et al. 2018

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Metals have crucial roles in many physiological, pathological, toxicological, pharmaceutical, and diagnostic processes. Proper handling of metal-containing macromolecule samples for structural studies is not trivial, and failure to handle them properly is often a source of irreproducibility caused by issues such as pH changes, incorporation of unexpected metals, or oxidization/reduction of the metal. This protocol outlines the guidelines and best practices for characterizing metal-binding sites in protein structures and alerts experimenters to potential pitfalls during the preparation and handling of metal-containing protein samples for X-ray crystallography studies. The protocol features strategies for controlling the sample pH and the metal oxidation state, recording X-ray fluorescence (XRF) spectra, and collecting diffraction data sets above and below the corresponding metal absorption edges. This protocol should allow experimenters to gather sufficient evidence to unambiguously determine the identity and location of the metal of interest, as well as to accurately characterize the coordinating ligands in the metal binding environment within the protein. Meticulous handling of metal-containing macromolecule samples as described in this protocol should enhance experimental reproducibility in biomedical sciences, especially in X-ray macromolecular crystallography. For most samples, the protocol can be completed within a period of 7-190 d, most of which (2-180 d) is devoted to growing the crystal. The protocol should be readily understandable to structural biologists, particularly protein crystallographers with an intermediate level of experience.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterizing metal-binding sites in proteins with X-ray crystallography

et al. 2018

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“…This led us to provide the 3 Å resolution model and also the full Pgp3 structure at 1.98 Å resolution as Supporting Information to allow consultation of the differences described. A similar situation was encountered in another study (Brink & Helliwell, 2017). This was resolved by placing a partial fully ordered structure in the PDB with a full model attached to the article.…”

Section: Data Collection and Processingmentioning

confidence: 80%

Chlamydia protein Pgp3 studied at high resolution in a new crystal form

Khurshid

Govada

Wills

et al. 2018

Int Union Crystallogr J

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Pgp3, a protein implicated in the sexually transmitted disease chlamydia, is described in a new crystal structure. It comprises a three-domain multi-macromolecular complex with two misaligned threefold axes; this comprised a unique challenge that has not been encountered before. A specific intermolecular interaction, possibly of functional significance in receptor binding in chlamydia, might allow the design of a new chemotherapeutic agent against chlamydia.

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“… There is a good utility of using two synchrotron X-ray wavelengths for element discrimination or enhanced sensitivity to lower metal atom occupancy; the variation in f “ is shown for simplicity. The arrows indicate the X-ray wavelengths used in measuring the diffraction datasets in the studies [ 60 , 61 ]. There is a variation also in f ‘ which must be allowed for in refining a metal atom occupancy.…”

Section: Exploring Examples Of Resultsmentioning

confidence: 99%

New developments in crystallography: exploring its technology, methods and scope in the molecular biosciences

Helliwell

2017

Bioscience Reports

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Since the Protein Data Bank (PDB) was founded in 1971, there are now over 120,000 depositions, the majority of which are from X-ray crystallography and 90% of those made use of synchrotron beamlines. At the Cambridge Structure Database (CSD), founded in 1965, there are more than 800,000 'small molecule' crystal structure depositions and a very large number of those are relevant in the biosciences as ligands or cofactors. The technology for crystal structure analysis is still developing rapidly both at synchrotrons and in home labs. Determination of the details of the hydrogen atoms in biological macromolecules is well served using neutrons as probe. Large multi-macromolecular complexes cause major challenges to crystallization; electrons as probes offer unique advantages here. Methods developments naturally accompany technology change, mainly incremental but some, such as the tuneability, intensity and collimation of synchrotron radiation, have effected radical changes in capability of biological crystallography. In the past few years, the X-ray laser has taken X-ray crystallography measurement times into the femtosecond range. In terms of applications many new discoveries have been made in the molecular biosciences. The scope of crystallographic techniques is indeed very wide. As examples, new insights into chemical catalysis of enzymes and relating ligand bound structures to thermodynamics have been gained but predictive power is seen as not yet achieved. Metal complexes are also an emerging theme for biomedicine applications. Our studies of coloration of live and cooked lobsters proved to be an unexpected favourite with the public and schoolchildren. More generally, public understanding of the biosciences and crystallography's role within the field have been greatly enhanced by the United Nations International Year of Crystallography coordinated by the International Union of Crystallography. This topical review describes each of these areas along with illustrative results to document the scope of each methodology.

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New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents

Abstract: The identification of multiple amino-acid coordination sites which can bind to the radiopharmaceutical synthon fac-[Re(CO)3]+ is reported.

Cited by 21 publications

References 55 publications

Characterizing metal-binding sites in proteins with X-ray crystallography

Characterizing metal-binding sites in proteins with X-ray crystallography

Chlamydia protein Pgp3 studied at high resolution in a new crystal form

New developments in crystallography: exploring its technology, methods and scope in the molecular biosciences

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