We have implemented the use of a heterobifunctional, UV photoactivatable cross-linker, which greatly increases the number of identified cross-links compared with homobifunctional, NHS-ester based cross-linkers. We have cross-linked human serum albumin in the context of human blood serum. We present a novel methodology that combines the use of this high-resolution cross-linking with conformational space search to investigate the structure of proteins in their native environment.