Unraveling allosteric landscapes of allosterome with ASD

Abstract

Allosteric regulation is one of the most direct and efficient ways to fine-tune protein function; it is induced by the binding of a ligand at an allosteric site that is topographically distinct from an orthosteric site. The Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) was developed ten years ago to provide comprehensive information related to allosteric regulation. In recent years, allosteric regulation has received great attention in biological research, bioengineering, and drug discovery, leading to the emergence of entire allosteric landscapes as allosteromes. To facilitate research from the perspective of the allosterome, in ASD 2019, novel features were curated as follows: (i) >10 000 potential allosteric sites of human proteins were deposited for allosteric drug discovery; (ii) 7 human allosterome maps, including protease and ion channel maps, were built to reveal allosteric evolution within families; (iii) 1312 somatic missense mutations at allosteric sites were collected from patient samples from 33 cancer types and (iv) 1493 pharmacophores extracted from allosteric sites were provided for modulator screening. Over the past ten years, the ASD has become a central resource for studying allosteric regulation and will play more important roles in both target identification and allosteric drug discovery in the future.

G protein-coupled receptors: structure- and function-based drug discovery

“…Allosteric modulators that enhance agonist-mediated response are called PAMs, while those attenuate the response are called NAMs. This phenomenon is very common such that the Allosteric Database 2019 (ASD, http://mdl.shsmu.edu.cn/ASD ) 162 records 37520 allosteric modulations on 118 GPCR members, covering all four classes.…”

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

“…Additionally, Sirt6 with mutations at the L116, R119, and S120 residues in Pocket X which most allosteric sites are identified from kinases and GPCRs, which hinders the performance of the prediction methods. Normal mode analysis-based approaches are restricted by their relatively coarse analysis procedures with limited accuracy and specificity during approximations 2,15,17,19,69,70 . Traditionally, the allosteric effect is defined as the modulation of the orthosteric sites by the allosteric sites.…”

“…Previously, allosteric drugs were identified mainly through serendipitous discovery due to difficulties in the identification and characterization of their binding sites2,14,15,20 . The rapid development of computational tools to predict allosteric sites partially enabled overcoming these limitations17,[68][69][70] . However, most sites predicted using these computational tools were associated with several limitations…”

Discovery of Latent Drivers from Double Mutations in Pan-Cancer Data Reveal their Clinical Impact

“…The impact of co-occurring mutations in the same gene is mostly additive but can be also cooperative. There are seven allosteric mutations at positions 83, 88, 365, 539, 542, 603, 629 in PIK3CA in BRCA as cataloged in Allosteric DB [49]. We found 23 significant double mutations in PIK3CA in the BRCA subtype of breast tumors.…”