Is the emperor wearing shorts? The published structures of ABC transporters

Abstract

ABC transporters use the energy of ATP binding and hydrolysis to transport substrates across cellular membranes. They comprise two highly conserved nucleotide binding domains and two transmembrane domains that form the transmembrane channel and contain the substrate binding sites. Structural analyses have found a variety of seemingly unrelated folds for the ABC transporter transmembrane domains, and from these, a set of diverse mechanistic models has been inferred. Nevertheless, in spite of the explosion in structure determination of ABC transporters in the last decade, advancement in certainty and clarity as to fundamental aspects of their molecular mechanisms remains elusive. With this in mind, here we put and examine the question: Could current ABC structures differ from the physiologic membrane-embedded forms?

Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology

“…The automatic detection of these states requires challenging text and 3D data mining methods and will be addressed in future studies. However, the experimental conditions during structure determination may influence the conformationally flexible ABC protein structures [ 60 , 61 ], thus correct classification. It also remained unresolved for the static ABC structure sets, and how to address protein dynamics [ 60 ].…”

“…However, the experimental conditions during structure determination may influence the conformationally flexible ABC protein structures [ 60 , 61 ], thus correct classification. It also remained unresolved for the static ABC structure sets, and how to address protein dynamics [ 60 ]. Extraction of protein motion using molecular dynamics simulations with the collected ABC structures is highly resource intensive [ 47 , 62 ].…”

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

“…At the same time, while atomic structures have been invaluable, they have to be interpreted with caution, especially when biochemistry or genetics are not in line with structural data [ 265 ] or when biological relevance appears doubtful. Indeed, the painful history of ABC transporter structures [ 207 , 265 ], shows that even higher resolution structures suffer from their static nature that only reflects snapshots of a catalytic cycle. Thus, we need atomic structures reflecting more than a single conformation and possibly many transition states [ 352 ], as well as extensive validation by biochemistry and genetics, to validate their biological relevance and define catalytic cycles.…”

“…[188][189][190] MDL1 * P33310 695 Peptides [191,192] STE6 P12866 1290 a-factor [193,194] S. pombe HMT1 * Q02592 830 Phytochelatin conjugated Cd2+ [195,196] MAM1 P78966 1336 M-factor [195,196] ABCC Collectively, P-gp, MRP1 and ABCG2 act as brothers in arms to ensure the physiological detoxification of endogenous metabolites as well as exogenous xenobiotics across most epithelial barriers, including placenta, testis, mammary epithelium, liver and GI tract as well as the blood-brain barrier [119,139,146,152,206]. However, how, and sometimes even if, they actually cause clinical MDR in cancer has remained a highly controversial issue, often subject to intense discussions in the field [102,207]. As for microbial anti-infective MDR, it has been generally accepted though that bacterial ABC transporters [208][209][210][211][212] and fungal PDR transporters [124,[213][214][215][216] are key causes for clinical MDR, often setting an unsurmountable roadblock in antimicrobial treatments [10,101,[217][218][219].…”

The incredible diversity of structures and functions of ABC transporters

“…While cryo‐EM produced structures at an astonishing pace, there was a cost, since structures could precede biochemical validation of deduced mechanisms. Several excellent papers in this special issue are dedicated to this controversy, arguing against the idea that the cryo‐EM snapshots can be straightforwardly interpreted and used to easily resolve many of the existing controversies within the ABC transporter field [5,6]. Importantly, cryo‐EM structures captured along the entire frame of the catalytic cycle confirm the long suspected conformational flexibility as a fundamental feature of ABC proteins [7].…”