Yu, C. W.-H. | Search bioRxiv

bioRxiv2026

PDBe-SIFTS: an open-source tool for Structure Integration with Function, Taxonomy, and Sequences, featuring improved alignment, scoring scheme, and accelerated search

Structure Integration with Function, Taxonomy and Sequences (SIFTS) provides residue-level mappings between UniProt Knowledgebase sequences and Protein Data Bank structures and has historically been generated through internal Protein Data Bank in Europe (PDBe) pipelines. Here, PDBe-SIFTS is presented as a fully open-source, locally deployable implementation of this mapping framework. The pipeline combines fast, scalable sequence search using MMseqs2, an improved bounded scoring scheme for ranking candidate mappings, and residue-level mapping refinement based on backbone connectivity. PDBe-SIFTS is distributed as a Python package with command-line tools for 1) building a sequence search database, 2) identifying the best sequence-structure match, 3) one-to-one mapping at the residue level, and 4) generating SIFTS annotations in PDBx/mmCIF format. Benchmarking on the complete Protein Data Bank archive showed that MMseqs2 reduced archive-scale UniProtKB searches from hours with BLASTP to minutes, approximately 22-36 times faster, while curated mappings were recovered at top rank in 93.1% of cases. The remaining discrepancies mainly involved biologically ambiguous cases such as highly conserved proteins, chimeric constructs, or closely related orthologs. These results show that PDBe-SIFTS enables fast mapping, improving structural coherence in residue-level alignments while delivering the most up-to-date and accurate mappings, comparable to expert curation. Tool: https://github.com/PDBeurope/SIFTS Quick start notebook with example: https://github.com/PDBeurope/SIFTS/tree/master/notebooks Broader audience statementMatching protein sequences to their three-dimensional structures, and mapping annotations across both, is essential for understanding protein function, interactions, and molecular mechanisms. This integrated view enables richer interpretation of biological data and underpins advances in drug discovery, disease research, and protein engineering. PDBe-SIFTS provides an open and functional framework for structure-sequence mapping, allowing researchers and databases to run, inspect, and extend these mappings locally, while benefiting from faster searches, transparent scoring, and structurally informed residue-level alignments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/721839v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@5e6ea6org.highwire.dtl.DTLVardef@1b2754dorg.highwire.dtl.DTLVardef@1334f9forg.highwire.dtl.DTLVardef@1b083a1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2021

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace

mTORC1 is a kinase complex regulating cell growth, proliferation and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTORs PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. Here we show, in contrast to previous cellular studies, that both the PDZ and linker regions are essential for inhibition, and it is likely that interaction with the FRB is crucial to the unique partial inhibition.

biochemistry↗