ABSTRACT: INTEGRATED STRUCTURAL BIOLOGY SHARED RESOURCE (ISBSR) The Sidney Kimmel Cancer Center (SKCC) Integrated Structural Biology Shared Resource (ISBSR) facilitates the design, acquisition, and interpretation of quantitative data relevant to the structure and function of cancer- related macromolecules, deciphers the impact of mutations on protein folding and stability, and promotes the understanding of macromolecular interactions at atomic detail. ISBSR represents the evolution of the X-Ray Crystallography and Macromolecular Characterization Shared Resource (XSR), established in 2009 and continuously funded by CCSG since. During the project period, SKCC expanded the scope of XSR to include cryogenic-electron microscopy (cryo-EM) and subsequently renamed the SR Integrated Structural Biology to reflect its expanded scope of services. The ISBSR provides access to high-end instrumentation as well as training and logistic support to conduct complex biophysical experiments. ISBSR operates a 200 kV Glacios cryo-electron microscope equipped with a Falcon 4 direct detector and also provides access to a Vitrobot G4 cryo-EM sample preparation station for fast and reproducible sample preparation. In addition, ISBSR continues to provide access to instrumentation for macromolecular characterization and crystallographic studies. The ISBSR is led by Director Gino Cingolani, PhD, who has over 25 years of research experience in biochemistry and structural biology. Cingolani helps users design and interpret experiments and oversees all instrumentation. PhD-level Facility Managers handle day-to-day operations, train users, help conduct experiments and analyze data. The ISBSR is located in Jefferson Alumni Hall and is easily accessible to all SKCC investigators via a short walk (<1 mile). The Specific Aims of the ISBSR are to: 1) Empower SKCC users to study biological systems top- down using cryogenic electron microscopy (cryo-EM) and single particle analysis, 2) Provide access to established methodologies to study biological macromolecules bottom-up through biophysical and crystallographic analysis, and 3) Train SKCC scientists and external users to conduct cancer-focused research using high-end biophysical instrumentation and guide them through the analysis and interpretation of structural data. During the project period, the ISBSR served 21 SKCC members, 8 (38.1%) of which had peer-reviewed funding, representing all four Research Programs. ISBSR services were utilized by 36 total users in 20 peer reviewed publications (average impact factor 14.27) and 11 grant applications. In line with the SKCC strategic plan, IMPACT PHL, and under the guidance of the Director and advisory boards, the ISBSR has set three goals for future development: 1) Expand the hardware and software for data storage, archiving, and transfer of cryo-EM micrographs, 2) Enhance the software and hardware for data collection of cryo-EM data by allowing on-the-fly analysis of cryo-micrographs, a...