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Cambridge MedChem Consulting

AlphaFold Protein Structure Database

The AlphaFold Protein Structure Database Developed by DeepMind and EMBL-EBI is now available online.

AlphaFold DB provides open access to protein structure predictions for the human proteome and 20 other key organisms to accelerate scientific research.

AlphaFold DB currently provides predicted structures for the organisms listed below and includes human, laboratory species, and key pathogens. All the predictions for all the species can be downloaded from the EBI FTP site ftp://ftp.ebi.ac.uk/pub/databases/alphafold.

Species Common Name Reference Proteome Predicted Structures Download
Arabidopsis thaliana Arabidopsis UP000006548 27,434 Download (3642 MB)
Caenorhabditis elegans Nematode worm UP000001940 19,694 Download (2601 MB)
Candida albicans C. albicans UP000000559 5,974 Download (965 MB)
Danio rerio Zebrafish UP000000437 24,664 Download (4141 MB)
Dictyostelium discoideum Dictyostelium UP000002195 12,622 Download (2150 MB)
Drosophila melanogaster Fruit fly UP000000803 13,458 Download (2174 MB)
Escherichia coli E. coli UP000000625 4,363 Download (448 MB)
Glycine max Soybean UP000008827 55,799 Download (7142 MB)
Homo sapiens Human UP000005640 23,391 Download (4784 MB)
Leishmania infantum L. infantum UP000008153 7,924 Download (1481 MB)
Methanocaldococcus jannaschii M. jannaschii UP000000805 1,773 Download (171 MB)
Mus musculus Mouse UP000000589 21,615 Download (3547 MB)
Mycobacterium tuberculosis M. tuberculosis UP000001584 3,988 Download (421 MB)
Oryza sativa Asian rice UP000059680 43,649 Download (4416 MB)
Plasmodium falciparum P. falciparum UP000001450 5,187 Download (1132 MB)
Rattus norvegicus Rat UP000002494 21,272 Download (3404 MB)
Saccharomyces cerevisiae Budding yeast UP000002311 6,040 Download (960 MB)
Schizosaccharomyces pombe Fission yeast UP000002485 5,128 Download (776 MB)
Staphylococcus aureus S. aureus UP000008816 2,888 Download (268 MB)
Trypanosoma cruzi T. cruzi UP000002296 19,036 Download (2905 MB)
Zea mays Maize UP000007305 39,299 Download (5014 MB)

The search bar at the top of the query page accepts queries based on protein name, gene name, UniProt identifier, or organism name. At present you can't search using a sequence and look for similar proteins. You would first need to do a BLAST search and use the results from that as queries.

Here I searched for Plasmodium falciparum carbonic anhydrase (Q8IHW5) a potential Malaria target. As you can see there is no crystal structure in the PDB. Whilst the active site is predicted with high confidence there are clearly regions for which there is very low confidence.

pfCAalphafold

You can then download the structure in PDB or mmCIF format.

I made a homology model (in purple below) of this protein a while back and it has little sequence similarity with any proteins in the PDB. Despite not including a Zinc the Alphafold Predicted Structure includes histidines in positions to potentially coordinate to the Zinc. If it is possible to include the Zinc in the structure prediction I'd be interested in finding out.

PfCA

Overall I'd say this is a very useful starting point.



How Structural Biologists and the Protein Data Bank Contributed to Recent FDA New Drug Approvals

An interesting review DOI

Discovery and development of 210 new molecular entities (NMEs; new drugs) approved by the US Food and Drug Administration 2010–2016 was facilitated by 3D structural information generated by structural biologists worldwide and distributed on an open-access basis by the PDB. The molecular targets for 94% of these NMEs are known. The PDB archive contains 5,914 structures containing one of the known targets and/or a new drug, providing structural coverage for 88% of the recently approved NMEs across all therapeutic areas. More than half of the 5,914 structures were published and made available by the PDB at no charge, with no restrictions on usage >10 years before drug approval. Citation analyses revealed that these 5,914 PDB structures significantly affected the very large body of publicly funded research reported in publications on the NME targets that motivated biopharmaceutical company investment in discovery and development programs that produced the NMEs.

Macrocycles in the Protein Data Bank

The Protein Data Bank is an absolutely invaluable resource, the PDB is an archive of 3D structural information of proteins, nucleic acids, and bimolecular complex assemblies. However it is much, much more than a simple archive, the submitted structures are curated and annotated to add information about protein ID, sequence information, organism, ligand details etc. This allows users to interrogate the database in many different ways. The database currently holds 141209 entries, with over 10,000 new entries added every year. The vast majority are X-ray crystal structures but there are now over 12,000 NMR derived structures.

The PDB also contains 25626 chemical components - 24007 as free ligands in 106374 PDB file and you can search via a web interface or download the structures in sdf file format. However browsing through the downloaded file it was apparently that macrocycles were not well represented. A discussion with the extraordinarily helpful Rachel Kramer Green at PDB revealed the issue. Basically any ligand containing more that two amino-acids is treated as a protein not a ligand, there are other rules to deal with modified amino-acids etc. but the bottom line is that the only way to get a comprehensive view of macrocycles in the PDB is to download the entire PDB and programmatically by parsing the entire data set.

First we need to decide what size ring constitutes a macrocycle. asking the "internet" failed to produce a definitive answer.

macrocyclesize

You can read the results and download the script here.

pdbMacrocycles

There is also a page that discusses macrocycles in drug discovery.

There is also an upcoming meeting on Macrocycles, 3rd RSC BMCS Medicinal Chemistry Symposium on Macrocycles. Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK. Full details are here http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm. #BMCS_Macrocycles

The objective of this symposium is to promote scientific interaction between scientists with a shared interest in the field of Macrocycles. This area is responsible for a growing number of therapeutic approaches and development candidates, all of which go ‘beyond the rule-of–five’. As a researcher in this field, come along to hear about the latest advances and also to share in some of the secrets of discovering therapeutic agents which go beyond Lipinski’s rules.