Kyle Brown
Faculty Member
Last active: 11/2/2017

Profile

The focus of my research is the elucidation of collagen-binding integrin structure/function mechanisms in order to understand their regulation in health and disease. Integrins are widely expressed, bidirectional signaling, transmembrane receptors essential for regulating cell growth and function. The diversity of diseases in which integrins play key roles, e.g. cancer metastasis, thrombosis, fibrosis, and diabetes, punctuates their biological importance and attractiveness as therapeutic targets. Notwithstanding their substantial potential, development of selective integrin therapeutics have been limited. Logically, rational drug design benefits from knowledge of structural mechanisms governing integrin function. The overarching question of "what is the molecular architecture of integrin-extracellular matrix (ECM) interactions and how are they disrupted in disease" guides my research. More specifically, I focus on the interactions between integrins a1b1 and a2b1 with collagens and laminins of the ECM. My philosophy is that direct observation of biological phenomena on an atomic level provides an essential basis for deciphering molecular interactions. Therefore, I subdivide my research to (1) determine integrin-ECM interactions with atomic resolution, (2) develop mechanistic models of integrin-ligand specificity and binding, (3) then test the impact of mutations and small molecules on these models. I utilize state-of-the-art biochemical, bioinformatic, structural, and computational technologies in conjunction with cell-based techniques to achieve these aims. Although initial observations are based on static structures, it is well known that motion is the basis for biological macromolecular function. While X-ray crystallography is a staple of my structural work, the innovation I bring to this endeavor is the integration of molecular dynamics simulations and NMR spectroscopy to provide time-resolved atomistic insight to integrin structure/function relationships. My ultimate goal is to use this information to guide development of more effective and safer therapeutic strategies for the treatment of fibrotic conditions.

Publications

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

Featured publications are shown below:

  1. Building collagen IV smart scaffolds on the outside of cells. Brown KL, Cummings CF, Vanacore RM, Hudson BG (2017) Protein Sci 26(11): 2151-2161
    › Primary publication · 28845540 (PubMed) · PMC5654846 (PubMed Central)
  2. Collagen IV and basement membrane at the evolutionary dawn of metazoan tissues. Fidler AL, Darris CE, Chetyrkin SV, Pedchenko VK, Boudko SP, Brown KL, Gray Jerome W, Hudson JK, Rokas A, Hudson BG (2017) Elife
    › Primary publication · 28418331 (PubMed)
  3. Extracellular chloride signals collagen IV network assembly during basement membrane formation. Cummings CF, Pedchenko V, Brown KL, Colon S, Rafi M, Jones-Paris C, Pokydeshava E, Liu M, Pastor-Pareja JC, Stothers C, Ero-Tolliver IA, McCall AS, Vanacore R, Bhave G, Santoro S, Blackwell TS, Zent R, Pozzi A, Hudson BG (2016) J Cell Biol 213(4): 479-94
    › Primary publication · 27216258 (PubMed) · PMC4878091 (PubMed Central)
  4. Hypohalous acids contribute to renal extracellular matrix damage in experimental diabetes. Brown KL, Darris C, Rose KL, Sanchez OA, Madu H, Avance J, Brooks N, Zhang MZ, Fogo A, Harris R, Hudson BG, Voziyan P (2015) Diabetes 64(6): 2242-53
    › Primary publication · 25605804 (PubMed) · PMC4439565 (PubMed Central)
  5. DNA Sequence Modulates Geometrical Isomerism of the trans-8,9- Dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)- 9-hydroxy Aflatoxin B1 Adduct. Li L, Brown KL, Ma R, Stone MP (2015) Chem Res Toxicol 28(2): 225-37
    › Primary publication · 25587868 (PubMed) · PMC4332041 (PubMed Central)
  6. Bypass of aflatoxin B1 adducts by the Sulfolobus solfataricus DNA polymerase IV. Banerjee S, Brown KL, Egli M, Stone MP (2011) J Am Chem Soc 133(32): 12556-68
    › Primary publication · 21790157 (PubMed) · PMC3154525 (PubMed Central)
  7. Structural perturbations induced by the alpha-anomer of the aflatoxin B(1) formamidopyrimidine adduct in duplex and single-strand DNA. Brown KL, Voehler MW, Magee SM, Harris CM, Harris TM, Stone MP (2009) J Am Chem Soc 131(44): 16096-107
    › Primary publication · 19831353 (PubMed) · PMC2773149 (PubMed Central)
  8. Inherent stereospecificity in the reaction of aflatoxin B(1) 8,9-epoxide with deoxyguanosine and efficiency of DNA catalysis. Brown KL, Bren U, Stone MP, Guengerich FP (2009) Chem Res Toxicol 22(5): 913-7
    › Primary publication · 19301826 (PubMed) · PMC3141577 (PubMed Central)
  9. Unraveling the aflatoxin-FAPY conundrum: structural basis for differential replicative processing of isomeric forms of the formamidopyrimidine-type DNA adduct of aflatoxin B1. Brown KL, Deng JZ, Iyer RS, Iyer LG, Voehler MW, Stone MP, Harris CM, Harris TM (2006) J Am Chem Soc 128(47): 15188-99
    › Primary publication · 17117870 (PubMed) · PMC2693076 (PubMed Central)