During his time as an undergraduate, McKnight worked in the laboratory of developmental biologist Gary Freeman, who encouraged him to apply to graduate school.
[5][6][7] After receiving his PhD in 1977, McKnight accepted a position as a Staff Associate at the Carnegie Institution of Washington’s Department of Embryology in Baltimore, Maryland.
[8] Don Brown, the far-sighted and charismatic leader of the Department of Embryology, had assembled a remarkable cadre of young scientists united in their determination to understand how genes are regulated and their devotion to a hands-on “small science” style of laboratory research.
McKnight’s work on eukaryotic promoters led him to the purification and study of gene-specific transcription factors, with particular emphasis on the manner in which they recognize their target DNA sequences.
McKnight purified and isolated cDNA coding for CCAAT/Enhancer Binding Protein (C/EBP), the founding member of a broad family of transcription factors, which includes those encoded by the Myc, Fos and Jun proto-oncogenes.
[11] Based on their studies of C/EBP, McKnight and his student William Landschulz, with independent contributions from Peter Kim and Erin O’Shea at MIT, defined the “basic leucine zipper” (bZIP) mode of DNA binding as a dimeric parallel coiled-coil in which amino acids in an adjacent basic region recognize a bipartite DNA target.
Peloton Therapeutics was acquired by Merck in 2019,[19] and its HIF2alpha inhibitor belzutifan was approved for therapy of renal cancer by the Food and Drug Administration (FDA) in 2023.
The weak cross-beta structures at the heart of protein phase separation are mediated by hydrogen bonding between polypeptide backbone N-H and carbonyl oxygen groups.
[30][31] Subtle mutations within the low complexity domain of TDP-43 enhance its self-association in a subset of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), thereby leading to the formation of protein aggregates in neurons of affected individuals.
In 1995, after three years as Director of Research at Tularik, Inc., a South San Francisco-based biotechnology company, McKnight moved to UTSW, serving as chair of the Department of Biochemistry from 1996 to 2016.