Alfred "Fred" Wittinghofer (born 23 May 1943) is a German biochemist.

At RWTH Aachen University he studied chemistry from 1963 with Diplom in 1968 and with doctorate (Promotion) in 1971. His doctoral work was done at RWTH Aachen University's Deutsches Wollforschungsinstitut (now called the DWI – Leibniz-Institut für Interaktive Materialien [de]). He worked from 1971 to 1973 as a postdoc at the University of North Carolina. At Heidelberg's Max Planck Institute for Medical Research he was 1974 from 1979 a scientific assistant and 1980 from 1993 a research group leader. In 1992 he completed his habilitation in biochemistry at the University of Heidelberg. At Dortmund's Max Planck Institute for Molecular Physiology, he was from 1993 to 2009 director of the structural biology department and from 2009 to 2016 "Emeritus Scientific Member" of the institute. From 1994 to 2009 he was Honorarprofessor for biochemistry at the Ruhr University Bochum.^[1][2]

Wittinghofer and colleagues examined the structure, function and mode of action of the oncogene product Ras.^[3][4][5]

Fred Wittinghofer has worked all his scientific life on the elucidation of structure-function relationships of GTP-binding proteins. He has shown how they function as molecular switches and how they perform their biological role by interacting with regulators and effectors. One of the more memorable contributions is the work on the oncoprotein Ras where he showed how the protein looks in 3D and how it interacts with downstream components and its GTPase Activating Protein (GAP) and why oncogenic mutants have a blockade in this switch-OFF reaction. Many more proteins of this class like Ran, Rap, Rho, Arl and Septins were investigated and their structure, function and biochemistry elucidated.^[1]

He has received at least a dozen honors and awards. He was elected in 1995 a member of the European Molecular Biology Organization (EMBO)^[6] and in 2001 a member of both Academia Europaea^[2] and the German National Academy of Sciences Leopoldina.^[1] He was awarded in 2001 the Louis-Jeantet Prize for Medicine,^[3] in 2003 the Otto Warburg Medal,^[7] and in 2019 the STS Honorary Medal from the Signal Transduction Society/Gesellschaft für Signaltransduktion and the International Journal of Molecular Sciences.^[8]

• Pai, Emil F.; Kabsch, Wolfgang; Krengel, Ute; Holmes, Kenneth C.; John, Jacob; Wittinghofer, Alfred (1989). "Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation". Nature. 341 (6239): 209–214. Bibcode:1989Natur.341..209P. doi:10.1038/341209a0. PMID 2476675. S2CID 4254449. (over 1050 citations)
• Saraste, Matti; Sibbald, Peter R.; Wittinghofer, Alfred (1990). "The P-loop — a common motif in ATP- and GTP-binding proteins". Trends in Biochemical Sciences. 15 (11): 430–434. doi:10.1016/0968-0004(90)90281-F. PMID 2126155. (over 2550 citations)
• Pai, E. F.; Krengel, U.; Petsko, G. A.; Goody, R. S.; Kabsch, W.; Wittinghofer, A. (1990). "Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 a resolution: Implications for the mechanism of GTP hydrolysis". The EMBO Journal. 9 (8): 2351–2359. doi:10.1002/j.1460-2075.1990.tb07409.x. PMC 552258. PMID 2196171. (over 1350 citations)
• Schlichting, Ilme; Almo, Steven C.; Rapp, Gert; Wilson, Keith; Petratos, Kyriakos; Lentfer, Arno; Wittinghofer, Alfred; Kabsch, Wolfgang; Pai, Emil F.; Petsko, Gregory A.; Goody, Roger S. (1990). "Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis". Nature. 345 (6273): 309–315. Bibcode:1990Natur.345..309S. doi:10.1038/345309a0. PMID 2111463. S2CID 4344306.
• Valencia, Alfonso; Chardin, Pierre; Wittinghofer, Alfred; Sander, Chris (1991). "The ras protein family: Evolutionary tree and role of conserved amino acids". Biochemistry. 30 (19): 4637–4648. doi:10.1021/bi00233a001. PMID 2029511.
• Nassar, Nicolas; Horn, Gudrun; Herrmann, Christian A.; Scherer, Anna; McCormick, Frank; Wittinghofer, Alfred (1995). "The 2.2 Å crystal structure of the Ras-binding domain of the serine/Threonine kinase c-Raf1 in complex with RaplA and a GTP analogue". Nature. 375 (6532): 554–560. Bibcode:1995Natur.375..554N. doi:10.1038/375554a0. PMID 7791872. S2CID 4347807.
• Scheffzek, Klaus; Ahmadian, Mohammad Reza; Kabsch, Wolfgang; WiesmüLler, Lisa; Lautwein, Alfred; Schmitz, Frank; Wittinghofer, Alfred (1997). "The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants". Science. 277 (5324): 333–339. doi:10.1126/science.277.5324.333. PMID 9219684. (over 1700 citations)
• De Rooij, Johan; Zwartkruis, Fried J. T.; Verheijen, Mark H. G.; Cool, Robbert H.; Nijman, Sebastian M. B.; Wittinghofer, Alfred; Bos, Johannes L. (1998). "Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP". Nature. 396 (6710): 474–477. Bibcode:1998Natur.396..474D. doi:10.1038/24884. PMID 9853756. S2CID 204996248. (over 2200 citations)
• Vetter, Ingrid R.; Wittinghofer, Alfred (2001). "The Guanine Nucleotide-Binding Switch in Three Dimensions". Science. 294 (5545): 1299–1304. Bibcode:2001Sci...294.1299V. doi:10.1126/science.1062023. PMID 11701921. S2CID 6636339. (over 2550 citations)
• Rocks, Oliver; Peyker, Anna; Kahms, Martin; Verveer, Peter J.; Koerner, Carolin; Lumbierres, Maria; Kuhlmann, JüRgen; Waldmann, Herbert; Wittinghofer, Alfred; Bastiaens, Philippe I. H. (2005). "An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms". Science. 307 (5716): 1746–1752. Bibcode:2005Sci...307.1746R. doi:10.1126/science.1105654. PMID 15705808. S2CID 12408991.
• Bos, Johannes L.; Rehmann, Holger; Wittinghofer, Alfred (2007). "GEFs and GAPs: Critical Elements in the Control of Small G Proteins". Cell. 129 (5): 865–877. doi:10.1016/j.cell.2007.05.018. PMID 17540168. S2CID 15798389. (over 1850 citations)

• "Alfred Wittinghofer (MPI) Part 1: GTP-binding Proteins as Molecular Switches". YouTube. iBiology. June 19, 2011.
• "Alfred Wittinghofer (MPI) Part 2: GTPase Reactions and Diseases". YouTube. iBiology. June 19, 2011.