HSP90 is a human chaperone involved in the folding of a wide variety of client proteins, including many oncogenic proteins. This complex molecular machinery is known to undergo massive conformational rearrangements throughout its functional cycle. X-ray crystallography and cryoEM have provided high-resolution snapshot structures of this human machinery in complex with cochaperones and client proteins, but have failed to provide the kinetic and time-resolved information needed for a full understanding of its mechanism. We plan to use NMR experiments combined with a new AI-enhanced analysis tool to obtain a detailed picture of the energy landscape of this important drug target. This project will provide structural information on the different excited states of HSP90 and the conformational dynamics between these states. In collaboration with the pharmaceutical industry, we will exploit this new approach to reveal how ligands can modulate the energy landscape and population of different functional states. This information will be particularly useful for the design of new drugs capable of blocking the HSP90 chaperone in a single state, an important step towards the development of more specific and effective drugs.