Elan Eisenmesser, PhD

The Eisenmesser lab takes a unique approach to understand protein function, and particularly enzyme function, by utilizing molecular engineering methods to control both structural interactions and the underlying movements that underlie their conformational changes.  The ultimate goal of the Eisenmesser lab is to fully characterize molecular interactions at both atomic resolution and biological levels with a particular emphasis on medically relevant systems that may be exploited to either block or promote events underlying disease progression. For example, we utilize NMR, X-ray crystallography, and cryo-EM methods together with biochemical and cellular biological studies to fully characterize molecular events that underlie molecular interactions involved in signaling and cellular homeostasis. Our approaches go well beyond static descriptions of molecular complexes to include the role of dynamics both within enzyme active sites and allosterically coupled movements that modulate function. In regard to enzyme movements, our studies have been cited as “the first attempt to rationally engineer enzyme motions” (see Peptide Letters, Doucet, 2011) and provide a critical means of unraveling how enzyme movements have evolved to perform specific tasks.

The current focus of the Eisenmesser lab are three projects described in what follows, which focus on:

1. understanding the molecular events of innate immunity that are tied to cancer and inflammatory activities at both the molecular and cellular levels
2. revealing the molecular details of how bacteria bind to host cells and modulate our innate immune system for infection
3. revealing both the structural and dynamic details of critical redox regulators in cellular function and cancer

Interleukin signaling on the outside of the cell and receptor interactions on the inside of the cell

Interleukins: Interleukins (IL) are a major class of cytokines responsible for regulating the innate immune response and their deregulation has been shown to occur during inflammation, cancer, and infection. The Eisenmesser lab is particularly focused on understanding the signaling events utilized by anti-inflammatory interleukins such as IL-37, in order to modulate their structure and biological activities and use as potential therapeutics. Such studies began during the PI’s postdoctoral work on IL-13 but have since been extended to other interleukins that include IL-8 and the anti-inflammatory interleukin-37.

Toll-Interleukin receptor (TIR) domains: TIR domains are conserved domains found within both interleukin-1 family receptors (IL-1Rs) and Toll-like family receptors, yet despite the 20 years since their discovery, their molecular interactions have eluded direct detection. The Eisenmesser lab is particularly focused on understanding how these TIR domains bridge signaling at the membrane surface with downstream interactions of adaptor TIR domains. While we are interested in determining the molecular interactions that occur at atomic resolution for pro-inflammatory TIRs, such as TLR1/2, we are also interested in understanding how IL-1R family receptors, such as those that include IL-1R8 that work to downregulate inflammation. Finally, we are also interested in understanding how bacteria utilize their own TIR domains to control host cell immunity through host cell TIR mimicry. 

Bacterial infection

Our interest in human infection and developing strategies to specifically block infection has fostered collaborative efforts to understand the molecular mechanisms of how bacteria thwart host cell immunity. Several ongoing projects include determining the molecular mechanism of the giant Streptococcus pneumonia IgA1 Protease, which is a metalloprotease like no other discovered to date, as well as small modules called G5 domains that mediate bacterial adherence. The uniqueness of the Streptococcus pneumonia IgA1 Protease was recently revealed by our study on the entire mature IgA1 Protease (res.154-1963) where we discovered a modular structure. For example, independently produced regions are well folded, which can be combined to produce an active enzyme and current studies are focused on structural studies. 

More recent studies have elucidated the structures of several independently folded G5 domains attached to giant membrane bound proteins on the surfaces of Streptococcus pneumonia. This G5 domain is present on the IgA1 Protease as well as several other membrane proteins (shown in figure) and are implicated in cellular adherence.  Thus, our studies are focused on elucidating the molecular mechanisms of bacterial giant proteases to develop vaccines to block infection, but also on G5 domains to block bacterial adherence that is becoming an increasing problem in hospitals where bacteria are found on medical devices.

Protein dynamics and function

We have made several major contributions to the field of protein dynamics, which have had direct implications for understanding of protein function, allostery, and have now allowed us to engineer enzyme dynamics in a rational way. The Eisenmesser lab is particularly interested in the interplay between structure and the dynamics that underlie conformational rearrangements of enzymes to direct their function. 

Our recent studies have focused on a key flavin reductase family of enzymes responsible for modulating cellular redox, called Biliverdin Reductase B (BLVRB), which are so important that they control cellular fate. We have discovered that enzyme dynamics modulate function up to 25 angstroms from the active site in human BLVRB, but we are focused on combining NMR and X-ray crystallography to determine how global motions modulate function in the entire family and how these motions have evolved. Such studies have revealed novel mechanisms of coenzyme regulation, revealing that coenzyme release is the rate-limiting step and that the single hydride modulates the global dynamic and structure.

Additional studies

The collaborative environment within the Department of Biochemistry & Molecular Genetics has fostered many collaborations, which include those with Dr. Hongin Zheng, Dr. Kirk Hansen, Dr. Angelo D’Alessandro, Dr. Rui Zhao, Dr. Jeff Kieft, and Dr. James DeGregori.  For example, multiple ongoing projects with the D’Alessandro lab are focused on key metabolic interactions governed by enzymes and we are highly focused on producing these enzymes to identify their atomic resolution details that govern their functions.