My work is focused on understanding the molecular basis of signaling mechanisms mediated by G proteins, which are switch proteins. G proteins are normally inactive, but a receptor that has received a specific signal can activate G proteins, leading to changes in the activity of enzymes that produce second messengers such as cyclic AMP and calcium.

The resulting changes in cellular activity underlie a large number of physiological processes. G protein-mediated signalling cascades are key regulators of many physiological processes, including processes of development, differentiation, and regulation of cell division. In the brain, many key neurotransmitters and neuromodulators mediate a myriad of functions by activation of such G protein cascades.

The research in my laboratory is aimed at understanding how G proteins become activated by receptors, how they in turn activate effector enzymes, and how they turn off. We determined the sites of interaction between proteins using a method of decomposing the proteins into small synthetic peptides and determining which peptides blocked interaction sites (Hamm et al., 1988; Rarick et al., 1992; Artemyev et al., 1993; Arshavsky et al., 1994). To understand the process more fully, we determined the atomic structure of the proteins in collaboration with the group of Paul Sigler. We used X-ray crystallography to solve the three-dimensional structures of G proteins in their inactive (GDP bound, (Lambright et al., 1994) and activated (GTPbgS-bound) forms (Noel et al., 1993). We caught a glimpse of the self-inactivating process in another crystal form, the transition state analog, Ga.GDP.AlF4- (Sondek et al., 1994). More recently, the structures of the bg subunit (Sondek et al., 1996) and the heterotrimeric G protein (Lambright et al., 1996) were solved. These high-resolution structural studies allowed us to postulate specific hypotheses regarding mechanisms of receptor:G protein interaction and activation, G protein subunit association-dissociation and effector activation.


The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. The hyperglycemic byproduct methylglyoxal impairs anticoagulant activity through covalent adduction of antithrombin III. Jacobson R, Mignemi N, Rose K, O'Rear L, Sarilla S, Hamm HE, Barnett JV, Verhamme IM, Schoenecker J (2014) Thromb Res 134(6): 1350-7
    › Primary publication · 25307422 (PubMed) · PMC4337957 (PubMed Central)
  2. Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354. Wen W, Young SE, Duvernay MT, Schulte ML, Nance KD, Melancon BJ, Engers J, Locuson CW, Wood MR, Daniels JS, Wu W, Lindsley CW, Hamm HE, Stauffer SR (2014) Bioorg Med Chem Lett 24(19): 4708-4713
    › Primary publication · 25176330 (PubMed) · PMC5716344 (PubMed Central)
  3. Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects. Cleator JH, Duvernay MT, Holinstat M, Colowick NE, Hudson WJ, Song Y, Harrell FE, Hamm HE (2014) J Pharmacol Exp Ther 351(1): 33-43
    › Primary publication · 25052834 (PubMed) · PMC4165026 (PubMed Central)
  4. A conserved phenylalanine as a relay between the α5 helix and the GDP binding region of heterotrimeric Gi protein α subunit. Kaya AI, Lokits AD, Gilbert JA, Iverson TM, Meiler J, Hamm HE (2014) J Biol Chem 289(35): 24475-87
    › Primary publication · 25037222 (PubMed) · PMC4148873 (PubMed Central)
  5. Differential localization of G protein βγ subunits. Betke KM, Rose KL, Friedman DB, Baucum AJ, Hyde K, Schey KL, Hamm HE (2014) Biochemistry 53(14): 2329-43
    › Primary publication · 24568373 (PubMed) · PMC4004276 (PubMed Central)
  6. Modulation of neurotransmission by GPCRs is dependent upon the microarchitecture of the primed vesicle complex. Hamid E, Church E, Wells CA, Zurawski Z, Hamm HE, Alford S (2014) J Neurosci 34(1): 260-74
    › Primary publication · 24381287 (PubMed) · PMC3866488 (PubMed Central)
  7. Energetic analysis of the rhodopsin-G-protein complex links the α5 helix to GDP release. Alexander NS, Preininger AM, Kaya AI, Stein RA, Hamm HE, Meiler J (2014) Nat Struct Mol Biol 21(1): 56-63
    › Primary publication · 24292645 (PubMed) · PMC3947367 (PubMed Central)
  8. G-protein-coupled receptors: evolving views on physiological signalling: symposium on G-protein-coupled receptors: evolving concepts and new techniques. Holinstat M, Oldham WM, Hamm HE (2006) EMBO Rep 7(9): 866-9
    › Primary publication · 16906127 (PubMed) · PMC1559677 (PubMed Central)
  9. Direct modulation of phospholipase D activity by Gbetagamma. Preininger AM, Henage LG, Oldham WM, Yoon EJ, Hamm HE, Brown HA (2006) Mol Pharmacol 70(1): 311-8
    › Primary publication · 16638972 (PubMed)
  10. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Cleator JH, Zhu WQ, Vaughan DE, Hamm HE (2006) Blood 107(7): 2736-44
    › Primary publication · 16332977 (PubMed) · PMC1895372 (PubMed Central)
  11. G betagamma binds histone deacetylase 5 (HDAC5) and inhibits its transcriptional co-repression activity. Spiegelberg BD, Hamm HE (2005) J Biol Chem 280(50): 41769-76
    › Primary publication · 16221676 (PubMed)
  12. RACK1 binds to a signal transfer region of G betagamma and inhibits phospholipase C beta2 activation. Chen S, Lin F, Hamm HE (2005) J Biol Chem 280(39): 33445-52
    › Primary publication · 16051595 (PubMed)
  13. RACK1 regulates specific functions of Gbetagamma. Chen S, Dell EJ, Lin F, Sai J, Hamm HE (2004) J Biol Chem 279(17): 17861-8
    › Primary publication · 14963031 (PubMed)