GUANINE-NUCLEOTIDE-EXCHANGE factors (GEFs) promote the exchange of GDP for GTP in Ras GTPases, and thereby positively regulate their functions1,2. Members of the Sec4/Yptl/Rab branch of the Ras superfamily are essential for vesicular transport3-6. A GEF for a subset of Rab proteins, termed mammalian suppressor of Sec4 (Mss4) has been identified7. Here we use multidimensional NMR to determine the structure of human Mss4 (hMss4), which is the first tertiary structure established for a protein with GEF activity. Mss4 contains a central β-sheet sandwiched between two small sheets. It also binds a Zn2+ ion through Cys 23, Cys 26, Cys 94 and Cys 97. The Rab-binding surface of hMss4 has subsequently been delineated using chemical-shift perturbation experiments and site-directed mutagenesis. The active site of hMss4 involves the Zn2+-binding region and a neighbouring loop.
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