AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

Váradi, Mihály; Anyango, Stephen; Deshpande, Mandar; Nair, Sreenath; Natassia, Cindy; Yordanova, Galabina; Yuan, David Yu; Stroe, Oana; Wood, Gemma; Laydon, Agata; Žídek, Augustin; Green, Tim; Tunyasuvunakool, Kathryn; Petersen, Stig; Jumper, John; Clancy, Ellen; Green, Richard; Vora, Ankur; Lutfi, Mira; Figurnov, Michael; Cowie, Andrew; Hobbs, Nicole; Kohli, Pushmeet; Kleywegt, Gerard J.; Birney, Ewan; Hassabis, Demis; Velankar, Sameer

doi:10.1093/nar/gkab1061

Cited by 5,583 publications

(5,129 citation statements)

References 20 publications

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“…Another 17% of the protein contains turns, 30% β-sheets, and 8% α-helices. Interestingly, secondary structure prediction methods as well as AlphaFold predict α-helices for the ordered CKAP2 segments ( Varadi et al, 2022 ). In contrast, our CD data predominantly show β-sheets as the main secondary structure element for CKAP2 in solution.…”

Section: Resultsmentioning

confidence: 99%

The mitotic spindle protein CKAP2 potently increases formation and stability of microtubules

McAlear

Bechstedt

2022

eLife

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Cells increase microtubule dynamics to make large rearrangements to their microtubule cytoskeleton during cell division. Changes in microtubule dynamics are essential for the formation and function of the mitotic spindle, and misregulation can lead to aneuploidy and cancer. Using in vitro reconstitution assays we show that the mitotic spindle protein Cytoskeleton-Associated Protein 2 (CKAP2) has a strong effect on nucleation of microtubules by lowering the critical tubulin concentration 100-fold. CKAP2 increases the apparent rate constant ka of microtubule growth by 50-fold and increases microtubule growth rates. In addition, CKAP2 strongly suppresses catastrophes. Our results identify CKAP2 as the most potent microtubule growth factor to date. These finding help explain CKAP2's role as an important spindle protein, proliferation marker, and oncogene.

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Section: Resultsmentioning

confidence: 99%

The mitotic spindle protein CKAP2 potently increases formation and stability of microtubules

McAlear

Bechstedt

2022

eLife

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“…After its dramatic emergence at the most recent CASP competition ( 28 ) the AlphaFold 2 (AF2) software for protein structure prediction was quickly published ( 29 ) released open source ( https://github.com/deepmind/alphafold ) and applied to the complete human proteome ( 30 ). Shortly after, the AlphaFold Protein Structure Database, described here ( 31 ), was released and covers 21 proteomes. The high-quality predicted structures in the database, projected to ultimately cover UniRef90 ( 32 ) protein sequence space, provide a treasure chest of information across all aspects of biology.…”

Section: New and Updated Databasesmentioning

confidence: 99%

The 2022Nucleic Acids Researchdatabase issue and the online molecular biology database collection

Rigden

Fernández

2021

Nucleic Acids Research

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The 2022 Nucleic Acids Research Database Issue contains 185 papers, including 87 papers reporting on new databases and 85 updates from resources previously published in the Issue. Thirteen additional manuscripts provide updates on databases most recently published elsewhere. Seven new databases focus specifically on COVID-19 and SARS-CoV-2, including SCoV2-MD, the first of the Issue's Breakthrough Articles. Major nucleic acid databases reporting updates include MODOMICS, JASPAR and miRTarBase. The AlphaFold Protein Structure Database, described in the second Breakthrough Article, is the stand-out in the protein section, where the Human Proteoform Atlas and GproteinDb are other notable new arrivals. Updates from DisProt, FuzDB and ELM comprehensively cover disordered proteins. Under the metabolism and signalling section Reactome, ConsensusPathDB, HMDB and CAZy are major returning resources. In microbial and viral genomes taxonomy and systematics are well covered by LPSN, TYGS and GTDB. Genomics resources include Ensembl, Ensembl Genomes and UCSC Genome Browser. Major returning pharmacology resource names include the IUPHAR/BPS guide and the Therapeutic Target Database. New plant databases include PlantGSAD for gene lists and qPTMplants for post-translational modifications. The entire Database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). Our latest update to the NAR online Molecular Biology Database Collection brings the total number of entries to 1645. Following last year's major cleanup, we have updated 317 entries, listing 89 new resources and trimming 80 discontinued URLs. The current release is available at http://www.oxfordjournals.org/nar/database/c/.

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“…This progress resulted in structure predictions for many integral membrane proteins such as hNTCP (Sequence Nr. : AF-Q14973-F1) allowing deeper understanding of protein folding, as well as the role of particular amino acids for molecule function and interactions ( Figure 2 ) [ 30 , 32 ].…”

Section: Ntcp: Structure and Transport Activitymentioning

confidence: 99%

Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery

Zakrzewicz

Geyer

2022

Biomedicines

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Hepatitis B virus (HBV) infections are among the major public health concerns worldwide with more than 250 million of chronically ill individuals. Many of them are additionally infected with the Hepatitis D virus, a satellite virus to HBV. Chronic infection frequently leads to serious liver diseases including cirrhosis and hepatocellular carcinoma, the most common type of liver cancer. Although current antiviral therapies can control HBV replication and slow down disease progress, there is an unmet medical need to identify therapies to cure this chronic infectious disease. Lately, a noteworthy progress in fighting against HBV has been made by identification of the high-affinity hepatic host receptor for HBV and HDV, namely Na+/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1). Next to its primary function as hepatic uptake transporter for bile acids, NTCP is essential for the cellular entry of HBV and HDV into hepatocytes. Due to this high-ranking discovery, NTCP has become a valuable target for drug development strategies for HBV/HDV-infected patients. In this review, we will focus on a newly predicted three-dimensional NTCP model that was generated using computational approaches and discuss its value in understanding the NTCP’s membrane topology, substrate and virus binding taking place in plasma membranes. We will review existing data on structural, functional, and biological consequences of amino acid residue changes and mutations that lead to loss of NTCP’s transport and virus receptor functions. Finally, we will discuss new directions for future investigations aiming at development of new NTCP-based HBV entry blockers that inhibit HBV tropism in human hepatocytes.

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AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

Cited by 5,583 publications

References 20 publications

The mitotic spindle protein CKAP2 potently increases formation and stability of microtubules

The mitotic spindle protein CKAP2 potently increases formation and stability of microtubules

The 2022Nucleic Acids Researchdatabase issue and the online molecular biology database collection

Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery

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