We present the results for CAPRI Round 46, the third joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo‐oligomers and 6 heterocomplexes. Eight of the homo‐oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higher‐order assemblies. These were more difficult to model, as their prediction mainly involved “ab‐initio” docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the nine easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance “gap” was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in template‐based modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements.

L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We crystallized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.

Aminocyclitols comprise an important group of compounds with remarkable biological activities. From a structural standpoint, aminocyclitols are amino polyhydroxy cycloalkanes that can be found in nature in several families of natural products. Among them, the aminoglycoside antibiotics, since the discovery of streptomycin, have become particularly relevant at the forefront of the antibacterial treatment. Another group of aminocyclitols, generally referred to as aminocarbasugars, have been found as key structural components of some families of alkaloids that have evolved as suitable leads for the development of potent glycosidase inhibitors with a vast array of applications in medicinal chemistry, both as therapeutically useful agents as well as valuable pharmacological tools. On the other hand, the aminocyclitol moiety has been used by medicinal chemists as a versatile scaffold in drug design. Thus, in the antiviral arena, it is found as the key component of several families of carbocyclic nucleoside analogues, designed as metabolically stable surrogates of the natural nucleosides. Finally, in a still relatively unexplored area, some aminocyclitol derivatives are being used as key components of artificial receptors for which promising applications in drug research can be envisaged. In all cases, the development of the modern regio- and stereoselective synthetic methodologies enables a large variety of stereochemically defined aminocyclitol analogues in order to study in depth the influence of this moiety on the structure-activity relationships from a given lead.