page_title: William Lipscomb
section_title: Large biological molecule structure and function
hierarchical_section_title: William Lipscomb / Scientific studies / Large biological molecule structure and function
caption_attribution_description: English: Structure refinement of fructose-1,6-bisphosphatase and its fructose 2,6-bisphosphate complex at 2.8 A resolution. Ke, H.M., Thorpe, C.M., Seaton, B., Lipscomb, W.N., Marcus, F.
context_page_description: William Nunn Lipscomb Jr. was a Nobel Prize-winning American inorganic and organic chemist working in nuclear magnetic resonance, theoretical chemistry, boron chemistry, and biochemistry.
context_section_description: Lipscomb's later research focused on the atomic structure of proteins, particularly how enzymes work.
  His group used x-ray diffraction to solve the three-dimensional structure of these proteins to atomic resolution, and then to analyze the atomic detail of how the molecules work.
  The images below are of Lipscomb's structures from the Protein Data Bank displayed in simplified form with atomic detail suppressed.  Proteins are chains of amino acids, and the continuous ribbon shows the trace of the chain with, for example, several amino acids for each turn of a helix.
  Carboxypeptidase A (left) was the first protein structure from Lipscomb's group.  Carboxypeptidase A is a digestive enzyme, a protein that digests other proteins.  It is made in the pancreas and transported in inactive form to the intestines where it is activated.  Carboxypeptidase A digests by chopping off certain amino acids one-by-one from one end of a protein.
  The size of this structure was ambitious.  Carboxypeptidase A was a much larger molecule than anything solved previously.
  Aspartate carbamoyltransferase.  (right) was the second protein structure from Lipscomb's group.
  For a copy of DNA to be made, a duplicate set of its nucleotides is required. Aspartate carbamoyltransferase performs a step in building the pyrimidine nucleotides (cytosine and thymidine).  Aspartate carbamoyltransferase also ensures that just the right amount of pyrimidine nucleotides is available, as activator and inhibitor molecules attach to aspartate carbamoyltransferase to speed it up and to slow it down.
  Aspartate carbamoyltransferase is a complex of twelve molecules.
  Six large catalytic molecules in the interior do the work, and six small regulatory molecules on the outside control how fast the catalytic units work.
  The size of this structure was ambitious.  Aspartate carbamoyltransferase was a much larger molecule than anything solved previously.
  Leucine aminopeptidase, (left) a little like carboxypeptidase A, chops off certain amino acids one-by-one from one end of a protein or peptide.
  HaeIII methyltransferase (right)
  binds to DNA where it methylates (adds a methy group to)
  it.
  Human interferon beta (left)
  is released by lymphocytes in response to pathogens to trigger the immune system.
  Chorismate mutase (right)
  catalyzes (speeds up) the production of the amino acids phenylalanine and tyrosine.
  Fructose-1,6-bisphosphatase (left)
  and its inhibitor MB06322 (CS-917)
  were studied by Lipscomb's group in a collaboration, which included Metabasis Therapeutics, Inc., acquired by Ligand Pharmaceuticals in 2010, exploring the possibility of finding a treatment for type 2 diabetes, as the MB06322 inhibitor slows the production of sugar by fructose-1,6-bisphosphatase.
  Lipscomb's group also contributed to an understanding of
  concanavalin A (low resolution structure),
  glucagon, and
  carbonic anhydrase (theoretical studies).
  Subsequent Nobel Prize winner Thomas A. Steitz
  was a doctoral student in Lipscomb's laboratory.
  Under Lipscomb's direction, after the training task of determining the structure of the small molecule methyl ethylene phosphate, Steitz made contributions to determining the atomic structures of carboxypeptidase A
  and aspartate carbamoyltransferase.
  
  Steitz was awarded the 2009 Nobel Prize in Chemistry for determining the even larger structure of the large 50S ribosomal subunit, leading to an understanding of possible medical treatments.
  Subsequent Nobel Prize winner Ada Yonath, who shared the 2009 Nobel Prize in Chemistry with Thomas A. Steitz and Venkatraman Ramakrishnan, spent some time in Lipscomb's lab where both she and Steitz were inspired to pursue later their own very large structures.  This was while she was a postdoctoral student at MIT in 1970.
caption: fructose-1,6-bisphosphatase
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